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Apixaban (Clinical considerations (Contraindications (Pregnancy…

- - - - Increases risk of bleeding
      - In controlled trials, orally administered Apixaban in healthy subjects at doses up to 50mg daily for 3-7days (25mg twice daily or 50mg once daily) had no clinically relevant side effects
  - - - Consult a drug interactions database for more specific and detailed information
        
        may require:
        
        frequency adjustment
        
        additional monitoring
        
        dose adjustment
        
        alternative therapy
        
        cytochrome P4503 A4 (CYP3A4) and/or P-glycoprotein (P-GP)
        
        Inducers
        
        such as carbamazepine, phenytoin and rifampicin
        
        increased the risk of stroke and/or embolism
        
        Inhibitors
        
        such as itraconazole, ketoconazole, clarithromycin and human immunodeficiency virus protease inhibitors
        
        increased the risk of bleeding
    - - Grapefruit
        
        may increase levels/effects
        
        management: if consume fruit or juice during treatment, monitor for increased bleeding
  - - - cerebral infarct
        
        ischemic
        
        hemorrhagic
      - spontaneous acquired impaired hemostasis
      - active peptic ulcer disease with recent bleeding
    - - except at doses used to maintain patency of central venous or arterial catheter
    - - Adverse effects not observed in animal reproduction studies
      - Expected to cross placenta
      - Because of insufficient data to evaluate safety of oral FXa inhibitors during pregnancy, use during pregnancy should be avoided
      - Breastfeeding
        
        may be present in breastmilk
        
        use of alternative anticoagulants is preferred
  - - - Renal impairment
        
        No dosage adjustment recommended by the manufacturer for any degree of renal impairment
        
        patients with a serum creatinine >2.5 mg/dL or CrCl <25 mL/minute were excluded from clinical trials
        
        some experts advise avoid use in severe renal impairment since efficacy remains untested and cannot be assured
      - Hepatic Impairment
        
        Moderate (Child-Pugh class B)
        
        no dosage adjustments provided in manufacturer's labeling; use with caution (limited clinical experience in these patients)
        
        Severe (Child-Pugh class C)
        
        Use not reccomended
        
        Mild (Child-Pugh class A)
        
        No dosage adjustment required
      - Geriatric
        
        ≥ 80 years old
        
        and either weighs ≤ 60 kg (132 lbs) or has a serum creatinine ≥ 1.5mg/dL
        
        reduce dose to 2.5mg twice daily
      - Obesity
        
        avoid use of all direct oral anticoagulants in patients with BMI >40 kg/m2 or weight >120 kg (265 lbs) due to the lack of clinical data in this population
        
        if use required, consider switch to a vit K antagonist
  - - - Tablet, Oral: 2.5mg
      - Tablet, Oral: 5mg
        
        Price
        
        $8.88/tablet
    - - Tablet, Oral: 5mg
  - - - Prophylaxis of DVT, which may lead to PE
        
        oral 2.5mg twice daily between 12 - 24 hours postoperatively
        
        Duration
        
        Optimal: unknown
        
        usually given minimum of 10-14 days and extended up to 35 days
    - - treatment of PE; reduce risk of recurrent PE following initial therapy
    - - reduce risk of stroke and systemic embolism
        
        oral 5mg twice daily
        
        UNLESS patient has any 2:
        
        body weight ≤ 60kg (132 lbs)
        
        reduce dose to 2.5mg twice daily
        
        serum creatinine ≥ 1.5mg/dL
        
        Age ≥ 80yo
    - - reduce risk of recurrent DVT following initial therapy
        
        oral 10mg twice daily for 7 days
        
        Following 5mg twice daily
        
        Duration
        
        Provoked VTE
        
        providing no risk factor is no longer present
        
        1 more item...
        
        Unprovoked PE or DVT
        
        ≥ 3 months
        
        1 more item...
        
        First episode
        
        optimal duration is unknown and depends on many factors
        
        4 more items...
        
        Indefinite therapeutic anticoagulation
        
        no specified stop date
        
        1 more item...
      - for initial therapy, without prior treatment with a parenteral anticoagulant in hemodynamically stable patients without extensive clot burden
      - as transition from parenteral anticoagulant
    - - Heparin-induced thrombocytopenia (HIT) treatment
        
        Level of evidence C, G
        
        studies suggest may be used in management of patients with HIT
        
        Duration
        
        Not well defined
        
        Minimum isolated HIT
        
        4 weeks
        
        MInimum HITT
        
        3 months
        
        HIT without thrombosis (isolated HIT)
        
        Oral 5mg twice daily
        
        HIT with Thrombosis (HITT)
        
        Initial: Oral 10mg twice daily for 7 days
        
        Followed by: 5mg twice daily
      - Recurrent stroke/transient ischemia attacks prevention
        
        Level of evidence G
        
        may be considered as an alternative to warfarin for the prevention of recurrent stroke or transient ischemic attack in patients with an acute MI complicated by left ventricular mural thrombus formation of anterior or apical wall-motion abnormalities with left ventricular ejection
  - - - only marketed drug at present
    - - discontinue drug
      - manual compression
      - maintain blood pressure
- - - - Surgical site bleeding may occur
  - - - hemorrhage may occur virtually at any site
        
        Risk is dependent on multiple variables including intensity of anticoagulation and patient susceptibility
  - - - Gastrointestinal
        
        3% nasea
        
        ≤1% gingival hemorrhage
      - Genitourinary
        
        ≤2% hematuria
        
        1%hypermenorrhea
      - Endocrine & metabolic
        
        ≤1% increased gamma-glutamyl transferase
      - Hematologic & oncologic
        
        3% anemia
        
        1-2% bruise
        
        1-2% hematoma
        
        ≤1% post procedural hemorrhage
        
        ≤1& rectal hemorrhage
      - Hepatic
        
        ≤1% increase serum transaminases
      - Respiratory
        
        ≤4% Epistaxis
        
        ≤1% hemoptysis
    - - Abnormal hepatic function tests, abnormal uterine bleeding, acute posthemorrhagic anemia, allergic edema, anal hemorrhage, anaphylaxis, conjunctival hemorrhage, gastrointestinal hemorrhage, genital bleeding, hematemesis, hematochezia, hematoma, hematoma at injection site, hemophthalmos, hemorrhoidal bleeding, hypersensitivity, hypotension, incision site hemorrhage, increased serum alkaline phosphatase, increased serum AST, increased serum bilirubin, intracranial hemorrhage, melena, muscle hemorrhage, occult blood in urine, perioperative blood loss, periorbital edema (Ahmad 2018), periorbital hematoma, petechia, postoperative hematoma (incision site), postprocedural hemorrhage, puncture site bleeding, retinal hemorrhage, skin rash, syncope, thrombocytopenia, vaginal hemorrhage, wound hemorrhage, wound secretion
    - - Hematological & Oncologic
        
        Hemorrhage
        
        2 -4% clinically relevant nonmajor
        
        <3% major
  - - - increase bleeding will occur during incase dental procedures
        
        Medical consult suggested before invasive procedures
      - Routine coagulation testing (INR) not required, or necessary, for DOAC
- - - - Major/Minor substrate status based on clinically relevant drug interaction potential
        
        CYP3A4/5 (major)
        
        CYP2C9 (minor)
        
        CYP2C8 (minor)
        
        into inactive metabolites
        
        major sites of transformation
        
        O-demethylation
        
        Hydroxylation
        
        CYP2C19 (minor)
        
        CYP1A2 (minor)
        
        BCRP/ABCG2
        
        P-glycoprotein/ABCB1
  - - - 3 - 4 hrs
    - - Steady state of volume distribution (Vss)
        
        Vss ~21 L
        
        reflects the actual blood and tissue volume into which a drug is distributed and the relative binding of drug to protein in these spaces
      - Protein binding
        
        ~87%
        
        molecule bound to protein is temporarily tied up and not available
        
        Creates a reservoir of potentially available drug for distribution
      - Bioavailability
        
        ~50%
    - - Half-life elimination
        
        ~ 12 hours (8-15)
      - Excretion
        
        Urine
        
        ~27% as parent drug
        
        Feces
        
        biliary and direct intestinal excretion
    - - No
    - - 1-2 hours
- - - - Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin