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Eliquis

Eliquis(apixaban) – Bristol-Myers

BOXED WARNING

May increase the risk of thrombotic events if therapy is d/c. Increase rate of stroke reported after d/c of therapy in patients with nonvalvular atrial fibrilation (A-fib). If therapy must be d/c for a reason other than pathological bleeding, consider coverage with another anticoagulant.

View FDA-Approved Full Prescribing Information for Eliquis

THERAPEUTIC CLASS

Specific factor Xa inhibitor

INDICATIONS

Reduce risk of stroke and systemic embolism in patients with nonvalvular A-fib.

ADULT DOSAGE

Adults: Usual: 5mg bid. In patients with any 2 of the following characteristics: ≥80 yrs, ≤60kg, or SrCr ≥1.5mg/dL: Usual: 2.5mg bid. With Strong Dual CYP3A4 and P-glycoprotein (P-gp) Inhibitors: Usual: 2.5mg bid. If already taking 2.5mg bid, avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp. Prior to Elective Surgery/Invasive Procedures: D/C at least 48 hrs prior to elective surgery or invasive procedures with moderate/high risk of unacceptable/clinically significant bleeding or at least 24 hrs with a low risk of bleeding or where bleeding would be noncritical in location and easily controlled. Refer to PI when switching from or to warfarin or other anticoagulants. Missed Dose: Refer to PI.

HOW SUPPLIED

Tab: 2.5mg, 5mg

CONTRAINDICATIONS

Active pathological bleeding.

WARNINGS/PRECAUTIONS

Not recommended in patients with severe hepatic impairment or with prosthetic heart valves. May increase risk of bleeding and may cause serious, potentially fatal bleeding. D/C with active pathological hemorrhage.

ADVERSE REACTIONS

Bleeding, hypersensitivity reactions, syncope.

DRUG INTERACTIONS

CYP3A4 and P-gp inhibitors may increase exposure and increase the risk of bleeding. CYP3A4 and P-gp inducers may decrease exposure and increase the risk of stroke. Avoid with strong dual inducers of CYP3A4 and P-gp (eg, rifampin, carbamazepine, phenytoin, St. John's wort). Avoid with strong dual inhibitors of CYP3A4 and P-gp (eg, ketoconazole, itraconazole, ritonavir, clarithromycin) in patients already taking 2.5mg apixaban bid. Increased risk of bleeding with drugs affecting hemostasis including aspirin (ASA) and other antiplatelets, other anticoagulants, heparin, thrombolytics, SSRIs, SNRIs, NSAIDs, and fibrinolytics.

PREGNANCY

Category B, not for use in nursing.

MECHANISM OF ACTION

Specific factor Xa (FXa) inhibitor; inhibits free and clot-bound FXa, and prothrombinase activity. Indirectly inhibits platelet aggregation induced by thrombin.

PHARMACOKINETICS

Absorption: Absolute bioavailability (50% [doses up to 10mg]); Tmax=3-4 hrs. Distribution: Vd=21L; plasma protein binding (87%). Metabolism: O-demethylation, hydroxylation via CYP3A4 (main contributor), CYP1A2, 2C8, 2C9, 2C19, and 2J2 (minor contributor). Elimination: Urine (27%), feces; T1/2=12 hrs (PO), 5 hrs (IV).

ASSESSMENT

Assess for drug hypersensitivity, active pathological bleeding, prescence of prosthetic heart valves, severe hepatic impairment, renal impairment, pregnancy/nursing status, and possible drug interactions. Obtain baseline SrCr.

MONITORING

Monitor for active pathological hemorrhage, stroke, thrombotic events, and other adverse reactions. Monitor renal function.

PATIENT COUNSELING

Instruct not to d/c without talking to physician first. Inform that it may take longer than usual to stop bleeding, and that may bruise and/or bleed more easily. Advise how to recognize bleeding/symptoms of hypovolemia and of the urgent need to report any unusual bleeding to physician. Instruct to inform physician and dentists if taking apixaban, and/or any other product known to affect bleeding, including OTC drugs (eg, ASA or NSAIDs), before any surgery or medical or dental procedure is scheduled and before any new drug is taken. Advise to inform physician if nursing/pregnant or intend to breastfeed or become pregnant. Inform that if a dose is missed, the dose should be taken as soon as possible on the same day and twice daily administration should be resumed. Inform that the dose should not be doubled to make up for a missed dose.

ADMINISTRATION/STORAGE

Administration: Oral route. Storage: 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F).


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    Eliquis

    Eliquis

    Generic Name: apixaban

    Dosage Form: tablet, film coated

    WARNING: DISCONTINUING Eliquis IN PATIENTS WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE Discontinuing Eliquis places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following discontinuation of Eliquis in clinical trials in patients with nonvalvular atrial fibrillation. If anticoagulation with Eliquis must be discontinued for a reason other than pathological bleeding, coverage with another anticoagulant should be strongly considered [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].

    Indications and Usage for Eliquis

    Eliquis® (apixaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

    Eliquis Dosage and Administration

    Recommended Dose

    The recommended dose of Eliquis for most patients is 5 mg taken orally twice daily.

    Dosage Adjustments

    The recommended dose of Eliquis is 2.5 mg twice daily in patients with any 2 of the following characteristics:

    • age ≥80 years
    • body weight ≤60 kg
    • serum creatinine ≥1.5 mg/dL

    CYP3A4 and P-gp inhibitors: When Eliquis is coadministered with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin), the recommended dose is 2.5 mg twice daily [see Clinical Pharmacology (12.3)].

    In patients already taking 2.5 mg twice daily, coadministration of Eliquis with strong dual inhibitors of CYP3A4 and P-gp should be avoided.

    Missed Dose

    If a dose of Eliquis is not taken at the scheduled time, the dose should be taken as soon as possible on the same day and twice daily administration should be resumed. The dose should not be doubled to make up for a missed dose.

    Discontinuation for Surgery and Other Interventions

    Eliquis should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. Eliquis should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily controlled.

    Converting from or to Eliquis

    Switching from warfarin to Eliquis: Warfarin should be discontinued and Eliquis started when the international normalized ratio (INR) is below 2.0.

    Switching from Eliquis to warfarin: Eliquis affects INR, so that INR measurements during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. If continuous anticoagulation is necessary, discontinue Eliquis and begin both a parenteral anticoagulant and warfarin at the time the next dose of Eliquis would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.

    Switching between Eliquis and anticoagulants other than warfarin: Discontinue one being taken and begin the other at the next scheduled dose.

    Hepatic Impairment

    No dose adjustment is required in patients with mild hepatic impairment.

    Because patients with moderate hepatic impairment may have intrinsic coagulation abnormalities and there is limited clinical experience with Eliquis in these patients, dosing recommendations cannot be provided [see Clinical Pharmacology (12.2)].

    Eliquis is not recommended in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

    Renal Impairment

    The dosing adjustment for moderate renal impairment is described above [see Dosage and Administration (2.2)]. No data inform use in patients with creatinine clearance <15 mL/min or on dialysis.

    Dosage Forms and Strengths

    • 2.5 mg, yellow, round, biconvex, film-coated tablets with “893” debossed on one side and “2½” on the other side.
    • 5 mg, pink, oval-shaped, biconvex, film-coated tablets with “894” debossed on one side and “5” on the other side.

    Contraindications

    Eliquis is contraindicated in patients with the following conditions:

    • Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]
    • Severe hypersensitivity reaction to Eliquis (i.e., anaphylactic reactions) [see Adverse Reactions (6.1)]

    Warnings and Precautions

    Increased Risk of Stroke with Discontinuation of Eliquis

    Discontinuing Eliquis in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from Eliquis to warfarin in clinical trials in patients with nonvalvular atrial fibrillation. If Eliquis must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant [see Dosage and Administration (2.3)].

    Bleeding

    Eliquis increases the risk of bleeding and can cause serious, potentially fatal, bleeding [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

    Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitor, and nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.3)].

    Patients should be made aware of signs and symptoms of blood loss and instructed to report them immediately or go to an emergency room. Eliquis should be discontinued in patients with active pathological hemorrhage.

    There is no established way to reverse the anticoagulant effect of apixaban, which can be expected to persist for about 24 hours after the last dose, i.e., for about two half-lives. A specific antidote for Eliquis is not available. Because of high plasma protein binding, apixaban is not expected to be dialyzable [see Clinical Pharmacology (12.3)]. Protamine sulfate and vitamin K would not be expected to affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is neither scientific rationale for reversal nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving apixaban. Use of procoagulant reversal agents such as prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa may be considered but has not been evaluated in clinical studies. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration [see Overdosage (10)].

    Patients with Prosthetic Heart Valves

    The safety and efficacy of Eliquis has not been studied in patients with prosthetic heart valves. Therefore, use of Eliquis is not recommended in these patients.

    Adverse Reactions

    The most serious adverse reactions reported with Eliquis were related to bleeding [see Warnings and Precautions (5.2)].

    Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

    The safety of Eliquis was evaluated in the ARISTOTLE and AVERROES studies [see Clinical Studies (14)], including 11,284 patients exposed to Eliquis 5 mg twice daily and 602 patients exposed to Eliquis 2.5 mg twice daily. The duration of Eliquis exposure was ≥12 months for 9375 patients and ≥24 months for 3369 patients in the two studies. In ARISTOTLE, the mean duration of exposure was 89 weeks (>15,000 patient-years). In AVERROES, the mean duration of exposure was approximately 59 weeks (>3000 patients-years).

    The most common reason for treatment discontinuation in both studies was for bleeding-related adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients treated with Eliquis and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on Eliquis and aspirin, respectively.

    Bleeding in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE and AVERROES Tables 1 and 2 show the number of patients experiencing major bleeding during the treatment period and the bleeding rate (percentage of subjects with at least one bleeding event per year) in ARISTOTLE and AVERROES.

    Major bleeding was defined as clinically overt bleeding that was accompanied by one or more of the following: a decrease in hemoglobin of 2 g/dL or more; a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least one of the following critical sites: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; or bleeding that was fatal. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.

    Table 1:     Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE
    Eliquis

    N=9088

    n (%/year)

    Warfarin

    N=9052

    n (%/year)

    Hazard Ratio

    (95% CI*)

    P-value
    *  Confidence interval.
       International Society on Thrombosis and Hemostasis (ISTH) major bleed assessed by sequential testing strategy for superiority designed to control the overall type I error in the trial.
       GI bleed includes upper GI, lower GI, and rectal bleeding.
    §   Intraocular bleed is within the corpus of the eye (a conjunctival bleed is not an intraocular bleed).
       Fatal bleed is an adjudicated death because of bleeding during the treatment period and includes both fatal extracranial bleeds and fatal hemorrhagic stroke.
    ** CRNM = clinically relevant nonmajor bleeding.
    Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.
    Major 327 (2.13) 462 (3.09) 0.69 (0.60, 0.80) <0.0001
        Gastrointestinal (GI) 128 (0.83) 141 (0.93) 0.89 (0.70, 1.14) -
        Intracranial 52 (0.33) 125 (0.82) 0.41 (0.30, 0.57) -
        Intraocular§ 32 (0.21) 22 (0.14) 1.42 (0.83, 2.45) -
        Fatal 10 (0.06) 37 (0.24) 0.27 (0.13, 0.53) -
    CRNM** 318 (2.08) 444 (3.00) 0.70 (0.60, 0.80) <0.0001

    In ARISTOTLE, the results for major bleeding were generally consistent across most major subgroups including age, weight, CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk), prior warfarin use, geographic region, Eliquis dose, type of AF, and aspirin use at randomization (Figure 1). Subjects treated with apixaban with diabetes bled more (3.0%/year) than did subjects without diabetes (1.9%/year).

    Figure 1:     Major Bleeding Hazard Ratios by Baseline Characteristics – ARISTOTLE Study

    Table 2:     Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in AVERROES
    Eliquis

    N=2978

    n (%/year)

    Aspirin

    N=2780

    n (%/year)

    Hazard Ratio

    (95% CI)

    P-value
    Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.
    Major 45 (1.41) 29 (0.92) 1.54 (0.96, 2.45) 0.07
        Fatal 5 (0.16) 5 (0.16) 0.99 (0.23, 4.29) -
        Intracranial 11 (0.34) 11 (0.35) 0.99 (0.39, 2.51) -

    Other Adverse Reactions Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and anaphylactic reactions, such as allergic edema) and syncope were reported in <1% of patients receiving Eliquis.

    Drug Interactions

    Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke.

    Strong Dual Inhibitors of CYP3A4 and P-gp

    The dose of Eliquis should be decreased to 2.5 mg twice daily when it is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp, (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

    In patients already taking Eliquis at a dose of 2.5 mg twice daily, avoid coadministration with strong dual inhibitors of both CYP3A4 and P-gp [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

    Strong Dual Inducers of CYP3A4 and P-gp

    Avoid concomitant use of Eliquis with strong dual inducers of CYP3A4 and P-gp (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban [see Clinical Pharmacology (12.3)].

    Anticoagulants and Antiplatelet Agents

    Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding.

    APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo. The rate of ISTH major bleeding was 2.77%/year with apixaban versus 0.62%/year with placebo in patients receiving single antiplatelet therapy and was 5.91%/year with apixaban versus 2.50%/year with placebo in those receiving dual antiplatelet therapy.

    In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on Eliquis from 1.8% per year to 3.4% per year and the bleeding risk on warfarin from 2.7% per year to 4.6% per year. In this clinical trial, there was limited (2.3%) use of dual antiplatelet therapy with Eliquis.

    USE IN SPECIFIC POPULATIONS

    Pregnancy

    Pregnancy Category B There are no adequate and well-controlled studies of Eliquis in pregnant women. Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. Eliquis should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus.

    Treatment of pregnant rats, rabbits, and mice after implantation until the end of gestation resulted in fetal exposure to apixaban, but was not associated with increased risk for fetal malformations or toxicity. No maternal or fetal deaths were attributed to bleeding. Increased incidence of maternal bleeding was observed in mice, rats, and rabbits at maternal exposures that were 19, 4, and 1 times, respectively, the human exposure of unbound drug, based on area under plasma-concentration time curve (AUC) comparisons at the maximum recommended human dose (MRHD) of 10 mg (5 mg twice daily).

    Labor and Delivery

    Safety and effectiveness of Eliquis during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using Eliquis in this setting [see Warnings and Precautions (5.2)].

    Treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with apixaban at a dose of 1000 mg/kg (about 5 times the human exposure based on unbound apixaban) did not result in death of offspring or death of mother rats during labor in association with uterine bleeding. However, increased incidence of maternal bleeding, primarily during gestation, occurred at apixaban doses of ≥25 mg/kg, a dose corresponding to ≥1.3 times the human exposure.

    Nursing Mothers

    It is unknown whether apixaban or its metabolites are excreted in human milk. Rats excrete apixaban in milk (12% of the maternal dose).

    Women should be instructed either to discontinue breastfeeding or to discontinue Eliquis therapy, taking into account the importance of the drug to the mother.

    Pediatric Use

    Safety and effectiveness in pediatric patients have not been established.

    Geriatric Use

    Of the total subjects in clinical studies of apixaban, >69% were 65 and older, and >31% were 75 and older. The effects of Eliquis on the risk of stroke and major bleeding compared to warfarin were maintained in geriatric subjects.

    Overdosage

    There is no antidote to Eliquis. Overdose of Eliquis increases the risk of bleeding [see Warnings and Precautions (5.2)].

    In controlled clinical trials, orally administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice-daily for 7 days or 50 mg once-daily 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. Mean apparent 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, indicating that charcoal blocked the continued absorption of apixaban from the gut [see Clinical Pharmacology (12.3)]. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion by leading to a more rapid fall in apixaban blood levels.

    Eliquis Description

    Eliquis (apixaban), a factor Xa (FXa) inhibitor, is chemically described as 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. Its molecular formula is C25H25N5O4, which corresponds to a molecular weight of 459.5. Apixaban has the following structural formula:

    Apixaban is a white to pale-yellow powder. At physiological pH (1.2-6.8), apixaban does not ionize; its aqueous solubility across the physiological pH range is ~0.04 mg/mL.

    Eliquis tablets are available for oral administration in strengths of 2.5 mg and 5 mg of apixaban with the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets).

    Eliquis – Clinical Pharmacology

    Mechanism of Action

    Apixaban is an oral, reversible, and selective active site inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, apixaban decreases thrombin generation and thrombus development.

    Pharmacodynamics

    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, however, are small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of apixaban.

    The Rotachrom® Heparin chromogenic assay was used to measure the effect of apixaban on FXa activity in humans during the apixaban development program. A concentration-dependent increase in anti-FXa activity was observed in the dose range tested and was similar in healthy subjects and patients with AF.

    This test is not recommended for assessing the anticoagulant effect of apixaban.

    Pharmacodynamic Drug Interaction Studies Pharmacodynamic drug interaction studies with aspirin, clopidogrel, aspirin and clopidogrel, enoxaparin, and naproxen were conducted. No pharmacodynamic interactions were observed with aspirin or clopidogrel, but a 50% to 60% increase in anti-FXa activity was observed when apixaban was coadministered with enoxaparin or naproxen.

    Specific Populations Renal impairment: Anti-FXa activity adjusted for exposure to apixaban was similar across renal function categories.

    Hepatic impairment: Changes in anti-FXa activity were similar in patients with mild to moderate hepatic impairment and healthy subjects. However, in patients with moderate hepatic impairment, there is no clear understanding of the impact of this degree of hepatic function impairment on the coagulation cascade and its relationship to efficacy and bleeding. Patients with severe hepatic impairment were not studied.

    Cardiac Electrophysiology Apixaban has no effect on the QTc interval in humans at doses up to 50 mg.

    Pharmacokinetics

    Apixaban displays prolonged absorption. Thus, despite a short clearance half-life of about 6 hours, the apparent half-life during repeat dosing is about 12 hours, which allows twice-daily dosing to provide effective anticoagulation, but it also means that when the drug is stopped for surgery, anticoagulation persists for at least a day.

    Absorption The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg of Eliquis. Food does not affect the bioavailability of apixaban. Maximum concentrations (Cmax) of apixaban appear 3 to 4 hours after oral administration of Eliquis. Apixaban is absorbed throughout the gastrointestinal tract with the distal small bowel and ascending colon contributing about 55% of apixaban absorption. 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.

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

    Metabolism Approximately 25% of an orally administered apixaban dose is recovered in urine and feces as metabolites. Apixaban is metabolized mainly via CYP3A4 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation.

    Unchanged apixaban is the major drug-related component in human plasma; there are no active circulating metabolites.

    Elimination Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of total clearance. Biliary and direct intestinal excretion contributes to elimination of apixaban in the feces.

    Following intravenous administration, apixaban is eliminated with a dominant half-life of ~5 hours. Following oral administration, the apparent half-life is ~12 hours because of prolonged absorption.

    Apixaban is a substrate of transport proteins: P-gp and breast cancer resistance protein.

    Drug Interaction Studies In vitro apixaban studies at concentrations significantly greater than therapeutic exposures, no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP3A4/5 or CYP2C19, nor induction effect on the activity of CYP1A2, CYP2B6 or CYP3A4/5 were observed. Therefore, apixaban is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp.

    The effects of coadministered drugs on the pharmacokinetics of apixaban and associated dose recommendations are summarized in Figure 2 [see also Warnings and Precautions (5.2) and Drug Interactions (7)].

    Figure 2:     Effect of Coadministered Drugs on the Pharmacokinetics of Apixaban

    *  Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing recommendations. Dosing recommendations were also informed by clinical considerations [see Warnings and Precautions (5.2) and Drug Interactions (7)].

    In dedicated studies conducted in healthy subjects, famotidine, atenolol, and enoxaparin did not meaningfully alter the pharmacokinetics of apixaban.

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

    Specific Populations The effects of level of renal impairment, age, body weight, level of hepatic impairment, gender, and ethnic origin on the pharmacokinetics of apixaban are summarized in Figure 3.

    Figure 3:     Effect of Specific Populations on the Pharmacokinetics of Apixaban

    *  Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing recommendations.

    A study in healthy subjects comparing the pharmacokinetics in males and females showed no meaningful difference.

    The results across pharmacokinetic studies in normal subjects showed no differences in apixaban pharmacokinetics among White/Caucasian, Asian, and Black/African American subjects. No dose adjustment is required based on race/ethnicity.

    Nonclinical Toxicology

    Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenesis: Apixaban was not carcinogenic when administered to mice and rats for up to 2 years. The systemic exposures (AUCs) of unbound apixaban in male and female mice at the highest doses tested (1500 and 3000 mg/kg/day) were 9 and 20 times, respectively, the human exposure of unbound drug at the MRHD of 10 mg/day. Systemic exposures of unbound apixaban in male and female rats at the highest dose tested (600 mg/kg/day) were 2 and 4 times, respectively, the human exposure.

    Mutagenesis: Apixaban was neither mutagenic in the bacterial reverse mutation (Ames) assay, nor clastogenic in Chinese hamster ovary cells in vitro, in a 1-month in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes, or in a rat micronucleus study in vivo.

    Impairment of Fertility: Apixaban had no effect on fertility in male or female rats when given at doses up to 600 mg/kg/day, a dose resulting in exposure levels that are 3 and 4 times, respectively, the human exposure.

    Apixaban administered to female rats at doses up to 1000 mg/kg/day from implantation through the end of lactation produced no adverse findings in male offspring (F1 generation) at doses up to 1000 mg/kg/day, a dose resulting in exposure that is 5 times the human exposure. Adverse effects in the F1-generation female offspring were limited to decreased mating and fertility indices at 1000 mg/kg/day.

    Clinical Studies

    ARISTOTLE

    Evidence for the efficacy and safety of Eliquis was derived from ARISTOTLE, a multinational, double-blind study in patients with nonvalvular atrial fibrillation (AF) comparing the effects of Eliquis and warfarin on the risk of stroke and non-central nervous system (CNS) systemic embolism. In ARISTOTLE, patients were randomized to Eliquis 5 mg orally twice daily (or 2.5 mg twice daily in subjects with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL) or to warfarin (targeted to an INR range of 2.0-3.0). Patients had to have one or more of the following additional risk factors for stroke:

    • prior stroke or transient ischemic attack (TIA)
    • prior systemic embolism
    • age ≥75 years
    • arterial hypertension requiring treatment
    • diabetes mellitus
    • heart failure ≥New York Heart Association Class 2
    • left ventricular ejection fraction ≤40%

    The primary objective of ARISTOTLE was to determine whether Eliquis 5 mg twice daily (or 2.5 mg twice daily) was effective (noninferior to warfarin) in reducing the risk of stroke (ischemic or hemorrhagic) and systemic embolism. Superiority of Eliquis to warfarin was also examined for the primary endpoint (rate of stroke and systemic embolism), major bleeding, and death from any cause.

    A total of 18,201 patients were randomized and followed on study treatment for a median of 89 weeks. Forty-three percent of patients were vitamin K antagonist (VKA) “naive,” defined as having received ≤30 consecutive days of treatment with warfarin or another VKA before entering the study. The mean age was 69 years and the mean CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk) was 2.1. The population was 65% male, 83% Caucasian, 14% Asian, and 1% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 19% of patients. Concomitant diseases of patients in this study included hypertension 88%, diabetes 25%, congestive heart failure (or left ventricular ejection fraction ≤40%) 35%, and prior myocardial infarction 14%. Patients treated with warfarin in ARISTOTLE had a mean percentage of time in therapeutic range (INR 2.0-3.0) of 62%.

    Eliquis was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism (Table 3 and Figure 4). Superiority to warfarin was primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with similar rates on both drugs.

    Eliquis also showed significantly fewer major bleeds than warfarin [see Adverse Reactions (6.1)].

    Table 3:     Key Efficacy Outcomes in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE (Intent-to-Treat Analysis)
    Eliquis

    N=9120

    n (%/year)

    Warfarin

    N=9081

    n (%/year)

    Hazard Ratio

    (95% CI)

    P-value
    The primary endpoint was based on the time to first event (one per subject). Component counts are for subjects with any event, not necessarily the first.
    Stroke or systemic embolism 212 (1.27) 265 (1.60) 0.79 (0.66, 0.95) 0.01
        Stroke 199 (1.19) 250 (1.51) 0.79 (0.65, 0.95)
            Ischemic without hemorrhage 140 (0.83) 136 (0.82) 1.02 (0.81, 1.29)
            Ischemic with hemorrhagic conversion 12 (0.07) 20 (0.12) 0.60 (0.29, 1.23)
            Hemorrhagic 40 (0.24) 78 (0.47) 0.51 (0.35, 0.75)
            Unknown 14 (0.08) 21 (0.13) 0.65 (0.33, 1.29)
        Systemic embolism 15 (0.09) 17 (0.10) 0.87 (0.44, 1.75)

    Figure 4:     Kaplan-Meier Estimate of Time to First Stroke or Systemic Embolism in ARISTOTLE (Intent-to-Treat Population)

    All-cause death was assessed using a sequential testing strategy that allowed testing for superiority if effects on earlier endpoints (stroke plus systemic embolus and major bleeding) were demonstrated. Eliquis treatment resulted in a significantly lower rate of all-cause death (p = 0.046) than did treatment with warfarin, primarily because of a reduction in cardiovascular death, particularly stroke deaths. Non-vascular death rates were similar in the treatment arms.

    In ARISTOTLE, the results for the primary efficacy endpoint were generally consistent across most major subgroups including weight, CHADS2 score (a scale from 0 to 6 used to predict risk of stroke in patients with AF, with higher scores predicting greater risk), prior warfarin use, level of renal impairment, geographic region, Eliquis dose, type of AF, and aspirin use at randomization (Figure 5).

    Figure 5:     Stroke and Systemic Embolism Hazard Ratios by Baseline Characteristics – ARISTOTLE Study

    AVERROES

    In AVERROES, patients with nonvalvular atrial fibrillation thought not to be candidates for warfarin therapy were randomized to treatment with Eliquis 5 mg orally twice daily (or 2.5 mg twice daily in selected patients) or aspirin 81 to 324 mg once daily. The primary objective of the study was to determine if Eliquis was superior to aspirin for preventing the composite outcome of stroke or systemic embolism. AVERROES was stopped early on the basis of a prespecified interim analysis showing a significant reduction in stroke and systemic embolism for Eliquis compared to aspirin that was associated with a modest increase in major bleeding (Table 4); [see Adverse Reactions (6.1)].

    Table 4:     Key Efficacy Outcomes in Patients with Nonvalvular Atrial Fibrillation in AVERROES
    Eliquis

    N=2807

    n (%/year)

    Aspirin

    N=2791

    n (%/year)

    Hazard Ratio

    (95% CI)

    P-value
    Stroke or systemic embolism 51 (1.62) 113 (3.63) 0.45 (0.32, 0.62) <0.0001
        Stroke
            Ischemic or undetermined 43 (1.37) 97 (3.11) 0.44 (0.31, 0.63) -
            Hemorrhagic 6 (0.19) 9 (0.28) 0.67 (0.24, 1.88) -
        Systemic embolism 2 (0.06) 13 (0.41) 0.15 (0.03, 0.68) -
    MI 24 (0.76) 28 (0.89) 0.86 (0.50, 1.48) -
    All-cause death 111 (3.51) 140 (4.42) 0.79 (0.62, 1.02) 0.068
        Vascular death 84 (2.65) 96 (3.03) 0.87 (0.65, 1.17) -

    How Supplied/Storage and Handling

    How Supplied Eliquis (apixaban) tablets are available as listed in the table below.

    Tablet

    Strength

    Tablet

    Color/Shape

    Tablet Markings Package Size NDC Code
    2.5 mg Yellow, round, biconvex Debossed with “893” on one side and “2½” on the other side Bottles of 60 0003-0893-21
    Bottles of 180 0003-0893-41    
    Hospital Unit-Dose Blister Package of 100 0003-0893-31
    5 mg Pink, oval, biconvex Debossed with “894” on one side and “5” on the other side Bottles of 60 0003-0894-21
    Bottles of 180 0003-0894-41  
    Hospital Unit-Dose Blister Package of 100 0003-0894-31

    Storage and Handling Store at 20°C to 25°C (68°F-77°F); excursions permitted between 15°C and 30°C (59°F-86°F) [see USP Controlled Room Temperature].

    Patient Counseling Information

    See FDA-approved patient labeling (Medication Guide).

    Advise patients of the following:

    • They should not discontinue Eliquis without talking to their physician first.
    • They should be informed that it might take longer than usual for bleeding to stop, and they may bruise or bleed more easily when treated with Eliquis. Advise patients about how to recognize bleeding or symptoms of hypovolemia and of the urgent need to report any unusual bleeding to their physician.
    • They should tell their physicians and dentists they are taking Eliquis, and/or any other product known to affect bleeding (including nonprescription products, such as aspirin or NSAIDs), before any surgery or medical or dental procedure is scheduled and before any new drug is taken.
    • They should tell their physicians if they are pregnant or plan to become pregnant or are breastfeeding or intends to breastfeed during treatment with Eliquis [see Use in Specific Populations (8.1, 8.3)].
    • If a dose is missed, the dose should be taken as soon as possible on the same day and twice daily administration should be resumed. The dose should not be doubled to make up for a missed dose.

    Manufactured by:

    Bristol-Myers Squibb Company

    Princeton, New Jersey 08543 USA

    Marketed by:

    Bristol-Myers Squibb Company

    Princeton, New Jersey 08543 USA

    and

    Pfizer Inc

    New York, New York 10017 USA

    Rotachrom® is a registered trademark of Diagnostica Stago.

    1289808 / 1298500 / 1289807

    Issued December 2012

    MEDICATION GUIDE

    Eliquis® (ELL eh kwiss)

    (apixaban)

    tablets

    What is the most important information I should know about Eliquis?

    • People with atrial fibrillation (a type of irregular heartbeat) are at an increased risk of forming a blood clot in the heart, which can travel to the brain, causing a stroke, or to other parts of the body. Eliquis lowers your chance of having a stroke by helping to prevent clots from forming. If you stop taking Eliquis, you may have increased risk of forming a clot in your blood.

      Do not stop taking Eliquis without talking to the doctor who prescribes it for you. Stopping Eliquis increases your risk of having a stroke.

      Eliquis may need to be stopped, if possible, prior to surgery or a medical or dental procedure. Ask the doctor who prescribed Eliquis for you when you should stop taking it. Your doctor will tell you when you may start taking Eliquis again after your surgery or procedure. If you have to stop taking Eliquis, your doctor may prescribe another medicine to help prevent a blood clot from forming.

    • Eliquis can cause bleeding which can be serious and rarely may lead to death. This is because Eliquis is a blood thinner medicine that reduces blood clotting.

      You may have a higher risk of bleeding if you take Eliquis and take other medicines that increase your risk of bleeding, including:

      • aspirin or aspirin-containing products
      • long-term (chronic) use of nonsteroidal anti-inflammatory drugs (NSAIDs)
      • warfarin sodium (COUMADIN®, JANTOVEN®)
      • any medicine that contains heparin
      • selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)
      • other medicines to help prevent or treat blood clots

      Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above.

      While taking Eliquis:

      • you may bruise more easily
      • it may take longer than usual for any bleeding to stop

      Call your doctor or get medical help right away if you have any of these signs or symptoms of bleeding when taking Eliquis:

      • unexpected bleeding, or bleeding that lasts a long time, such as:
        • unusual bleeding from the gums
        • nosebleeds that happen often
        • menstrual bleeding or vaginal bleeding that is heavier than normal
      • bleeding that is severe or you cannot control
      • red, pink, or brown urine
      • red or black stools (looks like tar)
      • cough up blood or blood clots
      • vomit blood or your vomit looks like coffee grounds
      • unexpected pain, swelling, or joint pain
      • headaches, feeling dizzy or weak
    • Eliquis is not for patients with artificial heart valves.

    What is Eliquis?

    Eliquis is a prescription medicine used to reduce the risk of stroke and blood clots in people who have atrial fibrillation.

    It is not known if Eliquis is safe and effective in children.

    Who should not take Eliquis?

    Do not take Eliquis if you:

    • currently have certain types of abnormal bleeding.
    • have had a serious allergic reaction to Eliquis. Ask your doctor if you are not sure.

    What should I tell my doctor before taking Eliquis?

    Before you take Eliquis, tell your doctor if you:

    • have kidney or liver problems
    • have any other medical condition
    • have ever had bleeding problems
    • are pregnant or plan to become pregnant. It is not known if Eliquis will harm your unborn baby.
    • are breastfeeding or plan to breastfeed. It is not known if Eliquis passes into your breast milk. You and your doctor should decide if you will take Eliquis or breastfeed. You should not do both.

    Tell all of your doctors and dentists that you are taking Eliquis. They should talk to the doctor who prescribed Eliquis for you, before you have any surgery, medical or dental procedure.

    Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way Eliquis works. Certain medicines may increase your risk of bleeding or stroke when taken with Eliquis. See “What is the most important information I should know about Eliquis?

    Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

    How should I take Eliquis?

    • Take Eliquis exactly as prescribed by your doctor.
    • Take Eliquis twice every day with or without food.
    • Do not change your dose or stop taking Eliquis unless your doctor tells you to.
    • If you miss a dose of Eliquis, take it as soon as you remember. Do not take more than one dose of Eliquis at the same time to make up for a missed dose.
    • Your doctor will decide how long you should take Eliquis. Do not stop taking it without first talking with your doctor. Stopping Eliquis may increase your risk of having a stroke.
    • Do not run out of Eliquis. Refill your prescription before you run out.
    • If you take too much Eliquis, call your doctor or go to the nearest hospital emergency room right away.
    • Call your doctor or healthcare provider right away if you fall or injure yourself, especially if you hit your head. Your doctor or healthcare provider may need to check you.

    What are the possible side effects of Eliquis?

    • See “What is the most important information I should know about Eliquis?
    • Eliquis can cause a skin rash or severe allergic reaction. Call your doctor or get medical help right away if you have any of the following symptoms:
      • chest pain or tightness
      • swelling of your face or tongue
      • trouble breathing or wheezing
      • feeling dizzy or faint

    Tell your doctor if you have any side effect that bothers you or that does not go away.

    These are not all of the possible side effects of Eliquis. For more information, ask your doctor or pharmacist.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store Eliquis?

    Store Eliquis at room temperature between 68°F to 77°F (20°C to 25°C).

    Keep Eliquis and all medicines out of the reach of children.

    General Information about Eliquis

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Eliquis for a condition for which it was not prescribed. Do not give Eliquis to other people, even if they have the same symptoms that you have. It may harm them.

    If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Eliquis that is written for health professionals.

    For more information, call 1-855-354-7847 (1-855-Eliquis) or go to www.Eliquis.com.

    What are the ingredients in Eliquis?

    Active ingredient: apixaban.

    Inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets).

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    Manufactured by:

    Bristol-Myers Squibb Company

    Princeton, New Jersey 08543 USA

    Marketed by:

    Bristol-Myers Squibb Company

    Princeton, New Jersey 08543 USA

    and

    Pfizer Inc

    New York, New York 10017 USA

    COUMADIN® is a registered trademark of Bristol-Myers Squibb Pharma Company.

    All other trademarks are property of their respective companies.

    1289808 / 1298500 / 1289807

    1295958

    Issued December 2012

    ———————————————

    REPRESENTATIVE PACKAGING

    See How Supplied section for a complete list of available packages of Eliquis.

    60 Tablets

    NDC 0003-0893-21

    Eliquis®

    (apixaban) tablets

    2.5 mg

    DISPENSE WITH MEDICATION GUIDE

    Rx only

    Bristol-Myers Squibb

    Pfizer

    60 Tablets

    NDC 0003-0894-21

    Eliquis®

    (apixaban) tablets

    5 mg

    DISPENSE WITH MEDICATION GUIDE

    Rx only

    Bristol-Myers Squibb

    Pfizer

    Eliquis 

    apixaban tablet, film coated

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0003-0893
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    apixaban (apixaban) apixaban 2.5 mg
    Inactive Ingredients
    Ingredient Name Strength
    anhydrous lactose  
    cellulose, microcrystalline  
    croscarmellose sodium  
    sodium lauryl sulfate  
    magnesium stearate  
    lactose monohydrate  
    hypromelloses  
    titanium dioxide  
    triacetin  
    ferric oxide yellow  
    Product Characteristics
    Color YELLOW Score no score
    Shape ROUND Size 6mm
    Flavor Imprint Code 893;2;1;2
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0003-0893-21 60 TABLET, FILM COATED in 1 BOTTLE, PLASTIC
    2 NDC:0003-0893-41 180 TABLET, FILM COATED in 1 BOTTLE, PLASTIC
    3 NDC:0003-0893-31 10 BLISTER PACK in 1 CARTON
    3 10 TABLET, FILM COATED in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA202155 12/28/2012
    Eliquis 

    apixaban tablet, film coated

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0003-0894
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    apixaban (apixaban) apixaban 5 mg
    Inactive Ingredients
    Ingredient Name Strength
    anhydrous lactose  
    cellulose, microcrystalline  
    croscarmellose sodium  
    sodium lauryl sulfate  
    magnesium stearate  
    lactose monohydrate  
    hypromelloses  
    titanium dioxide  
    triacetin  
    ferric oxide red  
    Product Characteristics
    Color PINK Score no score
    Shape OVAL Size 10mm
    Flavor Imprint Code 894;5
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0003-0894-21 60 TABLET, FILM COATED in 1 BOTTLE, PLASTIC
    2 NDC:0003-0894-41 180 TABLET, FILM COATED in 1 BOTTLE, PLASTIC
    3 NDC:0003-0894-31 10 BLISTER PACK in 1 CARTON
    3 10 TABLET, FILM COATED in 1 BLISTER PACK
    4 NDC:0003-0894-91 1 BLISTER PACK in 1 CARTON
    4 14 TABLET, FILM COATED in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA202155 12/28/2012
    Labeler - E.R. Squibb & Sons, L.L.C. (011550092)

    Revised: 12/2012   E.R. Squibb & Sons, L.L.C.

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    Eliquis

    Eliquis

    Generic Name: apixaban (a PIX a ban)

    Brand Name: Eliquis

    OverviewSide EffectsInteractionsMore…

    What is apixaban?

    Apixaban keeps the platelets in your blood from coagulating (clotting).

    Apixaban is used in people with atrial fibrillation (a heart rhythm disorder) to lower the risk of stroke caused by a blood clot.

    Apixaban may also be used for purposes not listed in this medication guide.

    What is the most important information I should know about apixaban?

    Because apixaban keeps your blood from coagulating (clotting) to prevent unwanted blood clots, this medicine can also make it easier for you to bleed, even from a minor injury such as a fall or a bump on the head. Avoid activities that may increase your risk of bleeding or injury. Contact your doctor or seek emergency medical attention if you have bleeding that will not stop.

    Call your doctor at once if you have any signs of bleeding such as weakness, feeling like you might pass out, easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin, pink or brown urine, bloody or tarry stools, coughing up blood, joint pain or swelling, or heavy menstrual bleeding.

    Tell any doctor or dentist who treats you that you are using apixaban. If you need surgery or dental work, you may need to stop using the medicine for a short time.

    Some drugs can raise or lower your blood levels of apixaban, which may cause side effects or make apixaban less effective. Many other drugs (including some over-the-counter medicines) can increase your risk of bleeding or life-threatening blood clots. It is very important to tell your doctor about all medicines you have recently used.

    Do not stop taking apixaban without first talking to your doctor. Stopping suddenly can increase your risk of blood clot or stroke.

    What should I discuss with my healthcare provider before taking apixaban?

    You should not take apixaban if you are allergic to it, if you have an artificial heart valve, or if you have any active bleeding from a surgery, injury, or other cause.

    Apixaban may cause you to bleed more easily, especially if you have a bleeding disorder that is inherited or caused by disease.

    To make sure apixaban is safe for you, tell your doctor if you have:

    • kidney disease;

    • liver disease;
    • if you are older than 80; or
    • if you weigh less than 132 pounds.

    FDA pregnancy category B. Apixaban is not expected to cause birth defects. However, taking this medicine during pregnancy may increase the risk of bleeding while you are pregnant or during your delivery. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

    It is not known whether apixaban passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

    How should I take apixaban?

    Apixaban is usually taken twice per day. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

    You may take apixaban with or without food.

    Because apixaban keeps your blood from coagulating (clotting) to prevent unwanted blood clots, this medicine can also make it easier for you to bleed, even from a minor injury such as a fall or a bump on the head. Contact your doctor or seek emergency medical attention if you fall or hit your head, or have any bleeding that will not stop.

    If you need surgery or dental work, tell the doctor or dentist ahead of time if you have taken apixaban within the past 24 hours. You may need to stop taking apixaban for a short time before you have surgery or other medical procedures.

    Do not stop taking this medication without first talking to your doctor. Stopping suddenly can increase your risk of blood clot or stroke.

    If you stop taking apixaban for any reason, your doctor may prescribe another medication to prevent blood clots until you start taking apixaban again.

    Use apixaban regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

    Store at room temperature away from moisture and heat.

    What happens if I miss a dose?

    Take the missed dose as soon as you remember. Take your next dose the following day and stay on your once-daily schedule. Do not take extra medicine to make up the missed dose.

    What happens if I overdose?

    Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

    What should I avoid while taking apixaban?

    Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

    Apixaban side effects

    Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

    Call your doctor at once if you have:

    • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), bleeding from wounds or needle injections, any bleeding that will not stop;

    • heavy menstrual periods;
    • headache, dizziness, weakness, feeling like you might pass out;
    • red, pink, or brown urine;
    • black or bloody stools, coughing up blood or vomit that looks like coffee grounds;
    • numbness, tingling, or muscle weakness (especially in your legs and feet); or
    • loss of movement in any part of your body.

    This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    See also: Eliquis side effects (in more detail)

    What other drugs will affect apixaban?

    Tell your doctor about all medicines you use, and those you start or stop using during your treatment with apixaban, especially:

    • bosentan;

    • conivaptan;
    • cyclosporine;
    • imatinib;
    • isoniazid, rifabutin, rifampin, rifapentine;
    • nefazodone;
    • St. John’s wort;
    • an antibiotic–azithromycin, clarithromycin, erythromycin, nafcillin, telithromycin;
    • antifungal medication–itraconazole, ketoconazole, posaconazole, voriconazole;
    • heart or blood pressure medication–amiodarone, captopril, carvedilol, diltiazem, dronedarone, felodipine, nicardipine, quinidine, ranolazine, verapamil;
    • the hepatitis C medications boceprevir or telaprevir;
    • HIV or AIDS medication–atazanavir, delavirdine, efavirenz, fosamprenavir, indinavir, nelfinavir, nevirapine, ritonavir, saquinavir, tipranavir; or
    • seizure medication–carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone.

    Many other drugs (including some over-the-counter medicines) can increase your risk of bleeding, or your risk of developing blood clots around the brain or spinal cord during a spinal tap or epidural. It is very important to tell your doctor about all medicines you have recently used, especially:

    • dextran;

    • abciximab, eptifibatide, ticagrelor, tirofiban;
    • alteplase, reteplase, tenecteplase, urokinase;
    • anagrelide, cilostazol, clopidogrel, dipyridamole, eltrombopag, oprelvekin, prasugrel, romiplostim, ticagrelor, ticlopidine;
    • argatroban, bivalirudin, dabigatran, lepirudin, rivaroxaban;
    • dalteparin, enoxaparin, fondaparinux, heparin, tinzaparin, warfarin, Coumadin;
    • an antidepressant such as citalopram, duloxetine, escitalopram, fluoxetine (Prozac), fluvoxamine, paroxetine, sertraline (Zoloft), trazodone, venlafaxine, vilazodone;
    • an NSAID (non-steroidal anti-inflammatory drug) such as ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib (Celebrex), diclofenac, indomethacin, meloxicam, and others; or
    • salicylates such as aspirin, Nuprin Backache Caplet, Kaopectate, KneeRelief, Pamprin Cramp Formula, Pepto-Bismol, Tricosal, Trilisate, and others.

    These lists are not complete and many other medicines can interact with apixaban. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

    Next Page → Side Effects

    More Eliquis resources

    • Side Effects
    • Pregnancy Warnings
    • Drug Images
    • Drug Interactions
    • Support Group
    • 0 Reviews - Add your own review/rating
    • Eliquis Prescribing Information (FDA)
    • Eliquis Consumer Overview

    Compare Eliquis with other medications

    • Prevention of Thromboembolism in Atrial Fibrillation

    Where can I get more information?

    • Your pharmacist can provide more information about apixaban.

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