Apixaban Accord 2,5 mg or 5 mg Tablet

Prevention of VTE : elective hip or knee replacement surgery

APIXABAN ACCORD is indicated for the prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.

Prevention of stroke and systemic embolism : nonvalvular atrial fibrillation (NVAF)

APIXABAN ACCORD is also indicated to reduce the risk of stroke, systemic embolism, and death in patients with nonvalvular atrial fibrillation with one or more risk factors.

Posology

Recommended dosage

Prevention of VTE: elective hip or knee replacement surgery

The recommended dose of APIXABAN ACCORD is 2,5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.

In patients undergoing hip replacement surgery, the recommended duration of treatment is 32 to 38 days.

In patients undergoing knee replacement surgery, the recommended duration of treatment is 10 to 14 days.

Prevention of stroke and systemic embolism: NVAF

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

Age, body weight, serum creatinine: In patients with at least 2 of the following characteristics, age u2265 80 years, body weight u2264 60 kg, or serum creatinine u2265 1,5 mg/dL (133 micromol/l), the recommended dose of APIXABAN ACCORD is 2,5 mg twice daily.

Special populations

Renal impairment

Prevention of VTE: elective hip or knee replacement surgery

In surgical patients no dose adjustment is necessary in patients with mild, moderate or severe (creatinine clearance 15-29 ml/min) renal impairment (see section 5.2). Because there is limited clinical experience in patients with creatinine clearance < 15 ml/min and there are no data in patients undergoing dialysis, APIXABAN ACCORD is not recommended in these patients (see section 4.4, Renal impairment, Prevention of VTE: elective hip or knee replacement surgery and Section 5.2).

Prevention of stroke and systemic embolism: NVAF

In patients with AF no dose adjustment is recommended in patients with creatinine clearance 15 to 29 ml/min, except as described under Section 4.2, Prevention of stroke and systemic embolism: NVAF. Because there is no clinical experience in patients with creatinine clearance < 15 ml/min, a dosing recommendation cannot be provided. There are no data in patients undergoing dialysis, therefore, APIXABAN ACCORD is not recommended in these patients.

Hepatic impairment

APIXABAN ACCORD may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment (see section 4.4, Hepatic impairment and section 5.2).

APIXABAN ACCORD is not recommended in patients with severe hepatic impairment (see section 4.4 and section 5.2).

Body weight

Prevention of VTE: elective hip or knee replacement surgery

No dose adjustment required (see section 5.2).

Prevention of stroke and systemic embolism: NVAF

See above under Recommended dosage, Prevention of stroke and systemic embolism: NVAF.

Elderly

Prevention of VTE: elective hip or knee replacement surgery

No dose adjustment required (see section 5.2).

Prevention of stroke and systemic embolism: NVAF

See above under Recommended dosage, Prevention of stroke and systemic embolism: NVAF.

Converting from or to parenteral anticoagulants

In general, switching treatment from parenteral anticoagulants to APIXABAN ACCORD (and vice versa) can be done at the next scheduled dose.

Converting from or to warfarin or other vitamin K antagonists (VKA)

When converting patients from warfarin or other VKA therapy to APIXABAN ACCORD, discontinue warfarin or other VKA therapy and start APIXABAN ACCORD when the INR is below 2,0.

When converting from APIXABAN ACCORD to warfarin or other VKA therapy, continue APIXABAN ACCORD for 48 hours after the first dose of warfarin or other VKA therapy.

Surgery and invasive procedures

APIXABAN ACCORD should be discontinued 2 to 3 days prior to elective surgery or invasive procedures such as neuraxial regional anaesthesia. If surgery or invasive procedures cannot be delayed, exercise appropriate caution taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.

Paediatric population

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

Method of administration

APIXABAN ACCORD can be taken with or without food. If a dose is missed, the patient should take APIXABAN ACCORD immediately and then continue with twice daily administration as before.

• Hypersensitivity to the active substance (apixaban) or to any of the excipients of APIXABAN ACCORD listed in section 6.1.
• Clinically significant active bleeding.
• APIXABAN ACCORD is not recommended in patients with severe renal disease (CrCI < 15 ml/min).
• APIXABAN ACCORD is not recommended in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
• APIXABAN ACCORD should not be administered with anti-platelet medicines other than aspirin (see section 4.4 and 4.5).

Haemorrhage risk

Patients taking APIXABAN ACCORD are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage, such as: congenital or acquired bleeding disorders; active ulcerative gastrointestinal disease; bacterial endocarditis; thrombocytopenia; platelet disorders; history of haemorrhagic stroke; severe uncontrolled hypertension; and recent brain, spinal, or ophthalmological surgery.

APIXABAN ACCORD administration should be discontinued if severe haemorrhage occurs (see sections 4.8 and 4.9).

Although treatment with apixaban does not require routine monitoring of exposure, a calibrated quantitative anti-Factor Xa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery (see section 5.1). There are no reversal medication for APIXABAN ACCORD.

Temporary discontinuation of APIXABAN ACCORD

Discontinue APIXABAN ACCORD, in the presence of active bleeding, elective surgery, or invasive procedures that place patients at an increased risk of haemorrhage. Lapses in therapy should be avoided and restart APIXABAN ACCORD therapy 12-24 hours after the danger of haemorrhage has ceased.

Interaction with other medicinal products affecting haemostasis

Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated (see section 4.3). The concomitant use of APIXABAN ACCORD with antiplatelet medicines increases the risk of bleeding (see section 4.5). Care is to be taken if patients are treated concomitantly with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), or non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid.

Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with APIXABAN ACCORD (see section 4.5). In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with APIXABAN ACCORD.

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

A patient with atrial fibrillation with (acute coronary syndrome) ACS and/or undergoing (percutaneous coronary intervention) PCI and a planned treatment period with a P2Y12 inhibitor, with or without ASA, and

APIXABAN ACCORD 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

Efficacy and safety of apixaban in the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) in patients with active cancer have not been established.

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 prevention of VTE in elective hip or knee replacement surgery (VTEp), the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), apixaban is to be used with caution in patients with severe renal impairment (creatinine clearance 15-29 mL/min) (see sections 4.2 and 5.2).

For the prevention of stroke and systemic embolism in patients with NVAF, patients with severe renal impairment (creatinine clearance 15-29 mL/min), and patients with serum creatinine u2265 1.5 mg/dL (133 micromole/L) associated with age u2265 80 years or body weight u2264 60 kg should receive the lower dose of apixaban 2.5 mg twice daily (see section 4.2).

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

Inhibitors of CYP3A4 and P-gp

Coadministration of apixaban with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean apixaban AUC and a 1.6-fold increase in mean apixaban Cmax. The use of APIXABAN ACCORD is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir) (see section 4.4).

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

Inducers of CYP3A4 and P-gp

Coadministration of apixaban with rifampicin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54 % and 42 % decrease in mean apixaban AUC and Cmax, respectively. The concomitant use of apixaban with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbitone 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 VTE in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE. Apixaban is not recommended for the treatment of DVT and PE in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised (see section 4.4).

Anticoagulants, platelet aggregation inhibitors, SSRIs/SNRIs and NSAIDs

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

After combined administration of enoxaparin (40 mg single dose) with apixaban (5 mg single dose), an additive effect on anti-Factor Xa activity was observed. Pharmacokinetic or pharmacodynamic interactions were not evident when apixaban was 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 Cmax, respectively. Corresponding increases in clotting tests were observed for apixaban. No changes were observed in the effect of naproxen on arachidonic acid-induced platelet aggregation and no clinically relevant prolongation of bleeding time was observed after concomitant administration of apixaban and naproxen. Despite these findings, there may be individuals with a more pronounced pharmacodynamic response when antiplatelet agents are co-administered with apixaban. APIXABAN ACCORD 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 (see section 4.4).

There is limited experience of co-administration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, co-administration of these medicinal products with APIXABAN ACCORD is not recommended (see section 4.4).

Other concomitant therapies

No clinically significant pharmacokinetic or pharmacodynamic 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 Cmax were 15 % and 18 % lower than when administered alone. The administration of apixaban 10 mg with famotidine 40 mg had no effect on apixaban AUC or Cmax.

Effect of apixaban on other medicinal products

In vitro apixaban studies showed no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 > 45 u03bcM) and weak inhibitory effect on the activity of CYP2C19 (IC50 > 20 u03bcM) at concentrations that are significantly greater than peak plasma concentrations observed in patients. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at a concentration up to 20 u03bcM. Therefore, apixaban is not expected to alter the metabolic clearance of coadministered medicinal products that are metabolised by these enzymes. Apixaban is not a significant inhibitor of P-gp.

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

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. Apixaban is not recommended 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. In rat milk, a high milk to maternal plasma ratio (Cmax about 8, AUC about 30) was found, possibly due to active transport into the milk. A risk to newborns and infants cannot be excluded. APIXABAN ACCORD treatment is not recommended for mothers who are breastfeeding their infants.

Fertility

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

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

a. Summary of the safety profile

Common adverse reactions were anaemia, haemorrhage, contusion, epistaxis, and haematoma (see Table 1 for adverse reaction profile and frequencies by indication).

b. Tabulated list of adverse reactions

Table 1 below shows the adverse reactions ranked under headings of system organ class and frequency

Table 1: ADRs

SYSTEM ORGAN CLASS

Prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery (VTEp)

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

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

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

Orally-administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily (bid) for 7 days or 50 mg once daily (od) for 3 days) had no clinically relevant adverse effects.

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

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

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