Eliquis

Apixaban.

Each film-coated tablet contains 2.5 mg and 5.0 mg apixaban, respectively.
Excipients/Inactive Ingredients: Each film-coated tablet contains 51.43 mg lactose (see Precautions).
Tablet Core - anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate.
Film Coat - lactose monohydrate, hypromellose, titanium dioxide, triacetin, and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets).

Pharmacology: Pharmacodynamics: 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 haemostasis.
Pharmacodynamic Effects: The pharmacodynarnic 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 phannacodynamic effects of apixaban.
Apixaban also demonstrates anti-FXa activity as evident by reduction in Factor Xa enzyme activity in the Rotachrom Heparin chromogenic assay. Anti-FXa activity exhibits a close direct linear relationship with apixaban plasma concentration, reaching maximum values at the time of apixaban peak plasma concentrations. The relationship between apixaban concentration and anti-FXa activity is linear over a wide dose range of apixaban, and precision of the Rotachrom assay is well within acceptable limits for use in a clinical laboratory. The dose- and concentration related changes observed following apixaban administration are more pronounced, and less variable, with anti-FXa activity compared with clotting tests.
Predicted steady-state peak and trough anti-FXa activity with apixaban 2.5 mg BID dosing are 1.3 IU/mL (5^th/95^th percentile 0.67-2.4 IU/mL) and 0.84 IU/mL (5^th/95^th percentile 0.37-1.8 IU/mL), respectively, demonstrating less than a 1.6-fold fluctuation in peak-to-trough anti-FXa activity over the dosing interval.
Table 1 shows the predicted steady-state exposure and anti-Factor Xa activity for each indication. In patients taking apixaban for the prevention of VTE following hip or knee replacement surgery, the results demonstrate a less than 1.6-fold fluctuation in peak-to- trough levels. In non-valvular atrial fibrillation patients taking apixaban for the prevention of stroke, the results demonstrate a less than 1.7-fold fluctuation in peak-to-trough levels.


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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.
Clinical Efficacy and Safety: Prevention of VTE: elective hip or knee replacement surgery: The apixaban clinical program was designed to demonstrate the efficacy and safety of apixaban for the prevention of VTE in a broad range of adult patients undergoing elective hip or knee replacement. A total of 8464 patients were randomized in two pivotal, double-blind, multinational studies, comparing apixaban 2.5 mg given orally twice daily or enoxaparin 40 mg once daily. Included in this total were 1262 patients of age 75 or older, 1004 patients with low body weight (≤60 kg), 1495 patients with BMI ≥33 kg/m² and 437 patients with severe or moderate renal impairment. The ADVANCE-3 study included 5407 patients undergoing elective hip replacement, and the ADVANCE-2 study included 3057 patients undergoing elective knee replacement. Subjects received either apixaban 2.5 mg given orally twice daily (po bid) or enoxaparin 40 mg administered subcutaneously once daily (sc od). The first dose of apixaban was given 12 to 24 hours post-surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Both apixaban and enoxaparin were given for 32-38 days in the ADVANCE-3 study and for 10-14 days in the ADVANCE-2 study.
Apixaban demonstrated a statistically superior reduction in the primary endpoint, a composite of all VTE/all cause death, and in the Major VTE endpoint, a composite of proximal DVT, non-fatal PE, and VTE-related death, compared to enoxaparin in both elective hip or knee replacement surgery (see Table 2).


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The safety endpoints of major bleeding, the composite of major and clinically relevant non-major (CRNM) bleeding, and all bleeding showed similar rates for patients treated with apixaban 2.5 mg compared with enoxaparin 40 mg (see Table 2). All the bleeding criteria included surgical site bleeding.
In both phase III studies, bleeding was assessed beginning with the first dose of double-blind study drug, which was either enoxaparin or injectable placebo, given 9 to 15 hours before surgery. Bleeding during the treatment period includes events that occurred before the first dose of apixaban, which was given 12 to 24 hours after surgery. Bleeding during the post-surgery treatment period only included events occurring after the first dose of study drug after surgery.
Over half the occurrences of major bleeding in the apixaban group occurred prior to the first dose of apixaban. Table 3 shows the bleeding results from the treatment period and the post-surgery treatment period. (See Table 3.)


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Prevention of stroke in patients with non-valvular atrial fibrillation (NVAF): A total of 23,799 patients were randomised in the clinical program (ARISTOTLE: apixaban versus warfarin, AVERROES: apixaban versus ASA) including 11,927 randomised to apixaban. The program was designed to demonstrate the efficacy and safety of apixaban for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and one or more additional risk factors, such as: prior stroke or transient ischaemic attack (TIA); age ≥75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II).
ARISTOTLE STUDY: In the ARISTOTLE study a total of 18,201 patients were randomized to double-blind treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [4.7%], see Dosage & Administration) or warfarin (target INR range 2.0-3.0), patients were exposed to 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 prior stroke or TIA.
In the study, apixaban achieved statistically significant superiority in the primary endpoint of prevention of stroke (haemorrhagic or ischaemic) and systemic embolism (see Table 4) compared with warfarin.


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For patients randomized to warfarin, the median percentage of time in therapeutic range (TTR) (INR 2-3) was 66%.
Apixaban showed a reduction of stroke and systemic embolism compared to warfarin across the different levels of center TTR; within the highest quartile of TTR according to center, the hazard ratio for apixaban vs warfarin was 0.73 (95% CI, 0.38, 1.40).
Key secondary endpoints of major bleeding and all cause death were tested in a pre-specified hierarchical testing strategy to control the overall type 1 error in the trial. Statistically significant superiority was also achieved in the key secondary endpoints of both major bleeding and all-cause death (see Table 5). With improving monitoring of INR the observed benefits of apixaban compared to warfarin regarding all cause death diminish.


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The overall discontinuation rate due to adverse reactions was 1.8% for apixaban and 2.6% for warfarin in the ARISTOTLE study.
The efficacy results for prespecified subgroups, including CHADS₂ score, age, body weight, gender, status of renal function, prior stroke or TIA and diabetes were consistent with the primary efficacy results for the overall population studied in the trial.
The incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) was 0. 76%/year with apixaban and 0.86%/year with warfarin.
The major bleeding results for prespecified subgroups including CHADS₂ score, age, body weight, gender, status of renal function, prior stroke or TIA and diabetes were consistent with the results for the overall population studied in the trial.
AVERROES STUDY: In the AVERROES study a total of 5,598 patients considered to be unsuitable for VKA by the investigators were randomized to treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [6.4%], see Dosage & Administration) or ASA. ASA was given at a once daily dose of 81 mg (64%), 162 (26.9%), 243 (2.1%), or 324 mg (6.6%) at the discretion of the investigator. Patients were exposed to 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 prior stroke or TIA.
Common reasons for unsuitability for VKA therapy in the AVERROES study included unable/unlikely to obtain INRs at requested intervals (42.6%), patient refused treatment with VKA (37.4%), CHADS₂ score =1 and physician did not recommend VKA (21.3%), patient could not be relied on to adhere to VKA medication instruction (15.0%), and difficulty/expected difficulty in contacting patient in case of urgent dose change (11.7%).
AVERROES was stopped early based on a recommendation by the independent Data Monitoring Committee due to clear evidence of reduction of stroke and systemic embolism with an acceptable safety profile.
The overall discontinuation rate due to adverse reactions was 1.5% for apixaban and 1.3% for ASA in the AVERROES study.
In the study, apixaban achieved statistically significant superiority in the primary endpoint of prevention of stroke (haemorrhagic, ischaemic or unspecified) or systemic embolism (see Table 6) compared to ASA.


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There was no statistically significant difference in the incidence of major bleeding between apixaban and ASA (see Table 7).


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Paediatric Population: The European Medicines Agency has deferred the obligation to submit the results of studies with ELIQUIS in one or more subsets of the paediatric population in venous and arterial embolism and thrombosis (see Dosage & Administration).
Pharmacokinetics: 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.
Distribution: Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 litres.
Metabolism 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 faeces. Renal excretion of apixaban accounts for approximately 27% of total clearance. Additional contributions from biliary and direct intestinal excretion were observed in clinical and non-clinical 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 drug-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).
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-FXa activity. No dose adjustment is necessary in patients with mild, moderate or severe renal impairment. There are no data available in patients with creatinine clearance <15 mL/min or in patients undergoing dialysis, therefore apixaban is not recommended in these patients (see Dosage & Administration and Precautions).
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.
Hepatic Impairment: Apixaban has not been studied in patients with severe hepatic impairment or active hepatobiliary disease.
Apixaban is not recommended in patients with severe hepatic impairment (see Precautions).
In a study comparing subjects with mild and moderate hepatic impairment (classified as Child Pugh A and B, respectively) to 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. No dose adjustment is required in patients with mild or moderate hepatic impairment; however, given the limited number of subjects studied, caution is advised when using ELIQUIS in this population (see Dosage & Administration and Precautions).
Elderly: Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 32% higher. No dose adjustment is required except as described in Dosage & Administration.
Gender: Exposure to apixaban was approximately 18% higher in females than in males. No dose adjustment is required.
Ethnic Origin and Race: The results across phase 1 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 consistent with the phase 1 results. No dose adjustment is required.
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. No dose adjustment is required except as described in Dosage & Administration.
Pharmacokinetic/pharmacodynamic relationship: The pharmacokinetic/pharmacodynamic (PK/PD) relationship between apixaban plasma concentration and several PD endpoints (anti-FXa activity, INR, PT, aPTT) has been evaluated after administration of a wide range of doses (0.5-50 mg). The relationship between apixaban concentration and factor Xa activity was best described by a linear model. The PK/PD relationship observed in patients who received apixaban following elective hip or knee replacement surgery was consistent with that established in healthy subjects.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, fertility and embryofoetal development (see Use in Pregnancy & Lactation). In the offspring of pregnant rats treated with apixaban, there were decreases in mating and fertility. These effects were minimal and observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.
The major observed effects in the repeated-dose toxicity studies were those related to the pharmacodynamic action of apixaban on blood coagulation parameters. In the toxicity studies, little to no increase of bleeding tendency was found. However, since this may be due to a lower sensitivity of the non-clinical species compared to humans, this result should be interpreted with caution when extrapolating to humans.

Prevention of VTE: elective hip or knee replacement surgery: Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.
Prevention of stroke: non-valvular atrial fibrillation: ELIQUIS is indicated to reduce the risk of stroke in patients with non-valvular atrial fibrillation with one or more risk factors, including patients unsuitable for warfarin/Vitarnin K antagonist therapy (VKA).

Prevention of VTE: elective hip or knee replacement surgery: The recommended dose of ELIQUIS 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 in patients with non-valvular atrial fibrillation (NVAF): The recommended dose of ELIQUIS is 5 mg taken orally twice daily.
Dose reduction: The recommended dose of ELIQUIS 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.
If a dose is missed, the patient should take ELIQUIS immediately and then continue with twice daily intake as before.
ELIQUIS can be taken with or without food.
Renal impairment: No dose adjustment is necessary in patients with mild or moderate renal impairment (see Pharmacology: Pharmacokinetics under Actions).
In patients with severe renal impairment (creatinine clearance 15-29 mL/min) the following recommendations apply (see Precautions and Pharmacology: Pharmacokinetics under Actions): Prevention of VTE: elective hip or knee replacement surgery: No dose adjustment is necessary in patients with mild, moderate or severe (creatinine clearance 15-29 mL/min) renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Prevention of stroke: NVAF: Patients should receive the lower dose of apixaban 2.5 mg twice daily.
Patients with serum creatinine ≥1.5 mg/dL (133 micromole/L) associated with age ≥80 years or body weight  ≤60 kg should also receive the lower dose of apixaban 2.5 mg twice daily.
In patients with creatinine clearance <15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore, apixaban is not recommended (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Body weight: Prevention of VTE: elective hip or knee replacement surgery: No dose adjustment required (see Pharmacology: Pharmacokinetics under Actions).
Prevention of stroke: NVAF: No dose adjustment required, unless criteria for dose reduction are met (see Dose reduction).
Gender: No dose adjustment required (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of ELIQUIS in children below age 18 have not yet been established. No data are available.
Elderly: Prevention of VTE: elective hip or knee replacement surgery: No dose adjustment required (see Pharmacology: Pharmacokinetics under Actions).
Prevention of stroke: NVAF: No dose adjustment required, unless criteria for dose reduction are met (see Dose reduction).
Cardioversion (NVAF): Patients can stay on apixaban while being cardioverted.
Switching: Switching treatment from parenteral anticoagulants to ELIQUIS (and vice versa) can be done at the next scheduled dose (see Interactions). These agents should not be administered simultaneously.
Switching from Vitamin K antagonist (VKA) therapy to Eliquis: When converting patients from Vitamin K antagonist (VKA) therapy to Eliquis, discontinue warfarin or other VKA therapy and start Eliquis when the international normalized ratio (INR) is <2.0.
Switching from Eliquis to VKA therapy: When converting patients from Eliquis to VKA therapy, continue administration of Eliquis for at least 2 days after beginning VKA therapy. After 2 days of coadministration of Eliquis with VKA therapy, obtain an INR prior to the next scheduled dose of Eliquis. Continue co-administration of Eliquis and VKA therapy until the INR is ≥2.0.

There is no antidote to ELIQUIS. Overdose of ELIQUIS 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 or the transfusion of fresh frozen plasma should be considered.
In controlled clinical trials, orally-administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg BID for 7 days or 50 mg QD for 3 days) [10 times the daily maximum recommended human dose] had no clinically relevant adverse effects.
A preclinical study in dogs demonstrated that oral administration of activated charcoal up to 3 hours after apixaban administration reduced apixaban exposure; therefore, activated charcoal may be considered in the management of apixaban overdose.
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. If life-threatening bleeding cannot be controlled by the above measures, administration of recombinant factor VIIa may be considered. However, there is currently 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.

Hypersensitivity to the active substance or to any of the excipients.
Clinically significant active bleeding.
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see Pharmacology: Pharmacokinetics under Actions).
Lesion or condition if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
Concomitant treatment with any other anticoagulant agent e.g., unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under specific circumstances of switching anticoagulant therapy (see Dosage & Administration) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see Interactions).

Haemorrhage risk: As with other anticoagulants, patients taking ELIQUIS are to be carefully observed for signs of bleeding.
ELIQUIS 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. ELIQUIS administration should be discontinued if severe haemorrhage occurs (see Overdosage).
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 Pharmacology: Pharmacodynamics under Actions).
Temporary discontinuation of ELIQUIS: Discontinuing anticoagulants, including ELIQUIS, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Avoid lapses in therapy, and if anticoagulation with ELIQUIS must be temporarily discontinued for any reason, restart therapy as soon as possible.
Renal impairment: Prevention of VTE: elective hip or knee replacement surgery: Because there is limited clinical experience in patients with creatinine clearance <15 mL/min, apixaban is not recommended in these patients (see Pharmacology: Pharmacokinetics under Actions).
Prevention of stroke : NVAF: Patients with severe renal impairment (creatinine clearance 15-29 mL/min), and patients with serum creatinine ≥1.5 mg/dL (133 micromole/L) associated with age ≥80 years or body weight ≤60 kg should receive the lower dose of apixaban 2.5 mg twice daily (see Dosage & Administration);
In patients with creatinine clearance <15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore, apixaban is not recommended (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Body weight: Low body weight (<60 kg) may increase haemorrhagic risk (see Pharmacology: Pharmacokinetics under Actions).
Hepatic Impairment: Eliquis is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see Contraindications).
ELIQUIS is not recommended in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
ELIQUIS may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (see Pharmacology: Pharmacokinetics under Actions).
Interaction with inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp): The use of Eliquis is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir). These medicinal products may increase apixaban exposure by 2-fold (see Interactions), 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 ELIQUIS with strong CYP3A4 and P-gp inducers (e.g., rifampin, 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 (see Interactions):
-for the prevention of VTE in elective hip or knee replacement surgery, for the prevention of stroke in patients with NVAF.
Interaction with other medicinal products affecting haemostasis: Care is to be taken if patients are treated concomitantly with medicinal products affecting Haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, platelet aggregation inhibitors or other antithrombotic agents (see Interactions).
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 ELIQUIS.
In a clinical trial 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 trial, there was limited (2.1%) use of concomitant dual antiplatelet therapy.
Spinal/epidural anaesthesia or puncture: When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of ELIQUIS. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to 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 is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
There is no clinical experience with the use of apixaban with indwelling intrathecal or epidural catheters. In case there is such need and based on pharmacokinetic data, a time interval of 20-30 hours (i.e., twice the half-life) between the last dose of apixaban and catheter withdrawal should elapse, and at least one dose should be omitted before catheter withdrawal. The next dose of apixaban may be given at least 5 hours after catheter removal. As with all new anticoagulant drugs, experience with neuraxial blockade is limited and extreme caution is therefore recommended when using apixaban in the presence of neuraxial blockade.
Hip fracture surgery: Apixaban has not been studied in clinical trials in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients. Therefore, ELIQUIS is not recommended in these patients.
Patients with prosthetic heart valves: Safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of ELIQUIS is not recommended in this setting.
Information about excipients: ELIQUIS contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Effects on ability to drive and use machines: ELIQUIS has no or negligible influence on the ability to drive and use machines.
Fertility: Studies in animals dosed directly with apixaban have shown no effect on fertility.
Elderly patients: Increasing age may increase haemorrhagic risk (see Pharmacology: Pharmacokinetics under Actions).
Also, the co-administration of Eliquis with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk.

Use in pregnancy: There are limited 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.
Use in lactation: 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 newborns and infants cannot be excluded.
A decision must be made to either discontinue breast-feeding or to discontinue/abstain from apixaban therapy.

Summary of the safety profile: The safety of apixaban has been investigated in 7 Phase III clinical studies including more than 21,000 patients: more than 5,000 patients in VTEp studies, 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 20 days, 1.7 years and 221 days respectively (see Pharmacology: Pharmacodynamics under Actions).
Common adverse reactions were haemorrhage, contusion, epistaxis, and haematoma (see Table 8 for adverse event profile and frequencies by indication).
In the VTEp studies, in total, 11% of the patients treated with apixaban 2.5 mg twice daily experienced adverse reactions. The overall incidence of adverse reactions related to bleeding with apixaban was 10% in the apixaban vs enoxaparin studies.
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 aspirin study. In the apixaban vs warfarin study the incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) with apixaban was 0.76%/year. The incidence of ISTH major intraocular bleeding with apixaban was 0.18%/year.
In the VTEt studies, the overall incidence of adverse reactions related to bleeding with apixaban was 15.6% in the apixaban vs enoxaparin/warfarin study and 13.3% in the apixaban vs placebo study (see Pharmacology: Pharmacodynamics under Actions).
Tabulated list of adverse reactions: Table 8 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 VTEp, NVAF, and VTEt respectively.


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The use of Eliquis may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which may result in posthaemorrhagic anaemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding (see Precautions and Pharmacology: Pharmacodynamics under Actions).

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. No dose adjustment for apixaban is required with concomitant ketoconazole therapy, however apixaban should be used with caution in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole or other strong inhibitors of both CYP3A4 and P-gp (see Precautions).
Active substances moderately inhibiting the apixaban elimination pathways, CYP3A4 and/or P-gp, are expected to increase apixaban plasma concentrations to a lesser extent. Diltiazem (360 mg once a day), for instance, 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. No dose adjustment for apixaban is required when co-administered with less potent inhibitors of CYP3A4 and/or P-gp.
Inducers of CYP3A4 and P-gp: Co-administration of apixaban with rifampin, 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 agents, however in patients receiving 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 and for the prevention of stroke in patients with NVAF.
Anticoagulants: 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.
Due to an increased bleeding risk, care is to be taken if patients are treated concomitantly with any other anticoagulants (see Precautions).
Platelet aggregation inhibitors and NSAIDs: Pharmacokinetic or pharmacodynamic interactions were not evident when apixaban was co-administered with acetylsalicylic acid 325 mg once a day.
Apixaban co-administered with clopidogrel (75 mg once a day) or with the combination of clopidogrel 75 mg and acetylsalicylic acid 162 mg once daily did not show a relevant increase in bleeding time, platelet aggregation, or clotting tests (PT, INR, and aPTT) compared to administration of the antiplatelet agents without apixaban.
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 pharmacodynamic response when antiplatelet agents are co-administered with apixaban. Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and/or platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk (see Precautions).
Agents associated with serious bleeding are not recommended concomitantly with Eliquis, such as: thrombolytic agents, GPIIb/IIIa receptor antagonists, thienopyridines (e.g., clopidogrel), dipyridamole, dextran and sulfinpyrazone.
Other concomitant therapies: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was co-administered with atenolol or famotidine. Co-administration 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 drugs 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.
Laboratory parameters: Clotting tests (eg, PT, INR and aPTT) are affected as expected by the mechanism of action of apixaban. Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability (see Pharmacology: Pharmacodynamics under Actions).
Paediatric population: Interaction studies have only been performed in adults.
Effect of apixaban on other drugs: In vitro apixaban studies showed no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 >45 µM) and weak inhibitory effect on the activity of CYP2C19 (IC50 >20 µM) at concentrations that are significantly greater than peak plasma concentrations observed in patients. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at a concentration up to 20 µM. Therefore, apixaban is not expected to alter the metabolic clearance of co-administered drugs that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp.
In studies conducted in healthy subjects, as described, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen or atenolol.
Digoxin: Co-administration 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: Co-administration 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: Co-administration of a single dose of apixaban (10 mg) and atenolol (100 mg), a common beta-blocker, did not alter the pharmacokinetics of atenolol.
Activated charcoal: Administration of activated charcoal reduces apixaban exposure (see Overdosage).

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Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AF02 - apixaban ; Belongs to the class of direct factor Xa inhibitors. Used in the treatment of thrombosis.

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