Apixaban (Brand Name Eliquis) is an oral anticoagulant that acts selectively by inhibiting clot-bound factor X reversibly and prevent platelet activation.

(Eliquis) Apixaban Uses:

• Apixaban for DVT (Deep vein thrombosis):

  • It is used in the treatment of deep vein thrombosis. It is also used to prevent future recurrence of venous thrombosis in patients who are at a high risk of developing thrombosis again (after the patient has been treated with a full dose for the acute symptoms).

• Apixaban in Non-valvular atrial fibrillation:

  • It is used in patients with non-valvular atrial fibrillation to prevent the occurrence of systemic embolization. Thus, it is used to prevent the occurrence of stroke and other embolic phenomena that might occur in these patients.
  • A recent observational study suggested that apixaban might be superior in preventing the incidence of systemic embolization and stroke in patients with non-valvular atrial fibrillation compared to rivaroxaban.
  • Furthermore, the same study also found apixaban to be superior in terms of safety outcomes including intracranial bleeding and gastrointestinal bleeding.

• Apixaban use in postoperative venous thromboprophylaxis after hip or knee replacement surgery:

  • It is used for the prevention of DVT and PE as a prophylactic treatment in patients who have undergone hip or knee replacement surgery.

• Pulmonary embolism:

  • It is used to treat patients with pulmonary embolism and to prevent the recurrence of PE following the initial treatment.

• Off Label Use of Apixaban in Adults:

  • It may be used in the treatment of Heparin-induced thrombocytopenia who are at a high risk of thrombosis
  • It may be used in the prevention of transient ischemic attacks and recurrent CVA.

Multaq and Eliquis (Dronaderone and apixaban):

Multaq is the brand name of dronedarone that is used in patients with cardiac arrhythmias. There have been concerns that Multaq in combination with apixaban or rivaroxaban may increase the risk of bleeding. However, in patients with atrial fibrillation, treated with either warfarin or apixaban, the incidences of bleeding were rare in patients treated simultaneously with Multaq (Dronaderone) [Ref].

Apixaban (Eliquis) in dental procedures (Dental Surgery):

In general, oral anticoagulants should not be stopped prior to dental procedures. However, in patients at risk of bleeding, apixaban should be stopped 24 hours prior to surgery. It is best to operate during the afternoon hours and the first few days of the week in case unpredicted bleeding occurs.

Dental surgery in patients on apixaban should be scantily traumatic and appropriate hemostatic measures should be adopted to control the bleeding. Post-operatively tranexamic acid may be used to stop the bleeding. In uncontrollable bleeding, andexanate alfa, activated charcoal, or prothrombin complex may be administered.

Apixaban and surgery (and procedures like colonoscopy):

Apixaban and the other oral anticoagulants have not been thoroughly studied in patients who undergo a surgical procedure. In general, surgery can be safely performed 24 hours after the last dose of apixaban. In high-risk patients such as the elderly and those with a creatinine of more than 1.5 mg/dl, it is best to perform the procedure after 48 hours.

In minor procedures like colonoscopy, apixaban may be continued but the procedure should be preferably done in the afternoon. Tranexamic acid may be given and local measures should be done to stop the bleeding. In uncontrollable bleeding, andexanate alfa, activated charcoal, or prothrombin complex may be required.

Apixaban (Eliquis) Vs Rivaroxaban (Xarelto):

Lastly, Apixaban can be safely used in patients with kidney disease while rivaroxaban is not recommended in patients with a CrCl of less than 30 ml/minute and should be used with caution in patients with a CrCl of less than 50 ml/minute.

Apixaban (Eliquis) Dose in Adults

Eliquis (Apixaban) Dose in the treatment of Heparin-induced thrombocytopenia:

• HIT with or without thrombosis:

  • 10 mg orally twice daily for 7 days or until the platelet count recovers, whichever is longer, followed by 5 mg twice daily.
  • It is given for 4 weeks to 3 months.
  • In patients with HIT with thrombosis, it is administered for 3 - 6 months.

Note:

• 10 mg twice daily may be given if the non-heparin parenteral anticoagulant is administered for less than 7 days.
• Patients who have received non-heparin parenteral anticoagulants for 7 days or more should be given apixaban in a dose of 5 mg twice daily.
• Some experts recommend 5 mg twice daily in all patients without thrombosis.

(Eliquis) Apixaban Dose in the treatment of Non-valvular atrial fibrillation to prevent stroke and systemic embolism:

• 5 mg orally twice daily unless the patient has any two of the following:
  • Aged 80 years or more,
  • Bodyweight is 60 kgs or less,
  • Serum creatinine is 1.5 mg/dL or more,
• The dose should be reduced to 2.5 mg two times a day if any of the above two are present.

(Apixaban) Eliquis Dose in the treatment of venous thromboembolism (VTE):

Treatment of Deep vein thrombosis or pulmonary embolism:

• Initial therapy:

  • In hemodynamically stable patients with no clot burden, apixaban may be administered without a parenteral anticoagulant or as a shift from parenteral anticoagulant.
  • 10 mg orally twice daily for seven days followed by 5 mg twice daily.

Note: A LMWH, edoxaban, or another suitable anticoagulant should be used in patients with active cancer.

• General recommendations regarding the duration of therapeutic anticoagulation after the first episode:

  • Provoked venous thromboembolism:

    • Three months (if the provoking risk factor is no longer present)

  • Unprovoked pulmonary embolism or Proximal or isolated distal DVT:

    • Depending on the risk of recurrence of thromboembolism and bleeding, anticoagulants may be given for 3 months or more.
    • Patients who require indefinite therapeutic anticoagulation should be assessed at regular intervals.

Eliquis Dose in patients who require indefinite anticoagulation (reduced-intensity dosing to prevent the recurrence of VTE):

Note: The reduced intensity regimen is not indicated in patients who require full therapeutic dose anticoagulation. For patients who have completed at least 6 months of full anticoagulation and are at an increased risk of recurrence.

• 2.5 mg orally twice daily

Eliquis Dose in the prophylaxis of VTE:

• As an alternative to LMWH in patients who have undergone a total hip arthroplasty or total knee arthroplasty:

  • 2.5 mg orally twice daily.
  • The treatment should be initiated at least 12 to 24 hours after the surgery.
  • The duration of prophylactic treatment should be given for a minimum of 10 to 14 days and may be extended for up to 35 days.
  • Some experts recommend treatment for 10 - 14 days in patients who have undergone TKA (total knee arthroplasty) and about 30 days in patients who have undergone THA (Total hip arthroplasty).

Apixaban (Eliquis) dosage in the transitioning between anticoagulants:

• Transitioning from a therapeutic dose of LMWH or fondaparinux to apixaban:

  • General shifting recommendation:

    • Apixaban should be initiated at the time of the next scheduled dose of the parenteral anticoagulant.

  • VTE initial treatment transition:

    • For acute venous thromboembolism, initiate apixaban within 6 to 12 hours after the last dose of a twice daily LMWH regimen or within 12 - 24 hours after a once daily regimen.

• Transitioning from continuous infusion of unfractionated heparin to apixaban:

  • Start apixaban treatment after the infusion is stopped.

• Transitioning from warfarin to apixaban:

  • When the INR is less than 2, warfarin treatment must be stopped and apixaban should be started.

• Transitioning from apixaban to continuous infusion unfractionated heparin, LMWH, or fondaparinux:

  • The parenteral anticoagulant should be started at the time of the next scheduled dose of apixaban.

• Transitioning from apixaban to warfarin:

  • INR interpretation may become difficult if treatment with warfarin is overlapped as Apixaban can increase the INR.
  • Two different approaches are being followed when initiating warfarin while on apixaban treatment.
    • One approach is to overlap apixaban for 2 or more days.
    • Another approach is to stop apixaban and start another parenteral anticoagulant along with warfarin until the desired INR is achieved.

• Transitioning from apixaban to another direct oral anticoagulant:

  • Start the new DOAC (direct oral anticoagulant) such as rivaroxaban when the next dose of apixaban was due to be given.

Dosage adjustment of apixaban (Eliquis) with concomitant medications:

• Concomitant use of a strong dual CYP3A4 and P-glycoprotein inhibitors such as ketoconazole, itraconazole, and ritonavir):

  • Decrease Apixaban dose by 50% in patients who require greater than 2.5 mg of apixaban twice daily.
  • Avoid concomitant use of these drugs in patients who require less than 2.5 mg twice daily.

• Strong dual CYP3A4 and P-glycoprotein inducers such as rifampin, carbamazepine, phenytoin, and St John's wort):

  • Avoid concomitant use of these medicines.

Apixaban (Eliquis) Dose in Childrens

 Safety and efficacy of the use of apixaban in children has not been established.

Eliquis in Pregnancy Risk Factor B

• Its use in pregnancy is not known. The drug could cross the placental boundary.
• It has been shown that oral factor Xa inhibitors do not increase the risk of adverse fetal outcomes in animal studies.
• Therefore, pregnant females should avoid using them.

Apixaban use during breastfeeding:

• It is unknown whether apixaban is excreted into breastmilk.
• Breastfeeding mothers should avoid apixaban, and instead use other anticoagulants.

Apixaban (Eliquis) dose in Renal impairment:

• Deep vein thrombosis, pulmonary embolism, and for the reduction in the risk of recurrent DVT and pulmonary embolism:

  • The manufacturer does not recommend any dose adjustment in patients with renal disease.
  • However, since it has not been studied in patients on hemodialysis and those with a creatinine of greater than 2.5 mg/dl or CrCl of less than 25 ml/min, some experts avoid using it in these patients.

• To prevent stroke and systemic embolism in patients with nonvalvular atrial fibrillation:

  • Serum creatinine of less than 1.5 mg/dL:

    • Adjustment in the dose is not necessary unless the patient is older than 80 years and the bodyweight is 60 kgs or less. Apixaban dose in these patients is reduced 2.5 mg twice daily.

  • Serum creatinine of 1.5 mg/dl or more and either the patient weighs 60 kgs or less or the age is 80 years or more.

    • 2.5 mg twice daily.

  • Severe or ESRD not requiring hemodialysis:

    • Warfarin is the drug of choice in these patients.
    • However, apixaban is a reasonable alternative.

  • ESRD requiring hemodialysis:

    • The manufacturer does not recommend adjusting the dose in patients with ESRD requiring hemodialysis unless the patient is 80 years of age or older or weighs 60 kgs or less. The dose is reduced to 2.5 mg twice daily in these patients.
    • Most experts recommend a lower dose of 2.5 mg twice daily in patients who require thrice-weekly hemodialysis.

• Renal dose adjustment in patients who require venous thromboprophylaxis after hip or knee replacement surgery:

  • The manufacturer does not recommend any dose adjustment in patients with any degree of renal impairment including ESRD.
  • However, it should be noted that apixaban has not been studied in patients with renal impairment in clinical trials.

• Additional recommendations:

  • Geriatric patients 65 years of age or older and a CrCl of less than 25 mL/minute:

    • Because of the increased risk of bleeding, it should be avoided.

Apixaban dosage in Liver disease:

• Mild impairment (Child-Pugh class A):

  • Adjustment in the dose is not required.

• Moderate impairment (Child-Pugh class B):

  • It should be used with caution in these patients.

• Severe impairment (Child-Pugh class C):

  • Avoid using apixaban.

Common Side Effects of Eliquis (Apixaban):

• Hematologic & oncologic:

  • Hemorrhage

Less Common Side Effects of Apixaban (Eliquis):

• Endocrine & metabolic:

  • Increased gamma-glutamyl transferase

• Gastrointestinal:

  • Nausea
  • Gingival hemorrhage

• Genitourinary:

  • Hematuria
  • Hypermenorrhea

• Hematologic & oncologic:

  • Anemia
  • Bruise
  • Hematoma
  • Postprocedural hemorrhage
  • Rectal hemorrhage

• Hepatic:

  • Increased serum transaminases

• Respiratory:

  • Epistaxis
  • Hemoptysis

Contraindication to Apixaban (Eliquis):

• Severe allergic reactions such as anaphylaxis and angioedema due to apixaban, or any component of it.
• Active pathological bleeding.
• High risk conditions such as hemorhagic or ischemic strokes, include those that are at higher risk of bleeding.
• Patients with a history of gastrointestinal bleeding have a higher chance of developing a peptic ulcer.
• Patients with impaired hemostasis
• A severe liver disease that causes coagulopathy
• Use of strong inhibitors of both CYP3A4 (P-glycoprotein) and CYP3A4 medications in conjunction
• Other anticoagulants may be used in conjunction with fondaparinux, low molecular weight Heparin and heparin derivatives (fondaparinux), as well as oral anticoagulants such as warfarin and dabigatran (except heparin) to maintain the patency intravenous lines, arterial catheters, and to transition to or from apixaban.

Warnings and precautions

• Bleeding

  • It apixaban, an anticoagulant is known to increase bleeding risk in elderly patients and high-risk individuals.
  • Patients who take concomitant anticoagulants such as NSAIDs or other anticoagulants are at greater risk of bleeding.
  • If there is any bleeding, it should be stopped immediately.
  • Andexanate alfa is able to stop life-threatening bleeding.
  • Apixaban, which is protein-bound, is not removed by hemodialysis if given to patients suffering from ESRD.
  • If the drug is ingested within 2 hours, activated charcoal may be given to reduce its absorption from the gastrointestinal tract.
  • Other options for andexanate alfa are:
    • Concentrate of unactivated 4-factor prothrombin, such as Kcentra
    • Concentrate of 4-factor activated protothrombin complex like FEIBA
  • A correction in the coagulation profile doesn't mean that the anticoagulation effects of the medication will be reversed.

• Events that are thromboembolic: [US Boxed Warning]

  • Premature discontinuation of anticoagulants can increase the risk of thrombotic episodes.
  • When apixaban is used to prevent stroke in patients with non-valvular atrial fibrillation, the risk of stroke is increased when the drug is transitioned from apixaban to warfarin in clinical trials.
  • Patients on apixaban and other DOAC who have suffered an acute ischemic stroke should be advised to stop taking oral anticoagulants for up to two weeks. 
  • Patients who have had a minor, non-disabling stroke or are at high risk for developing another thrombotic event should resume oral anticoagulation within three days. 
  • Patients who have suffered a severe stroke or major disability should not start oral anticoagulants for more than two weeks.

• Acute coronary syndrome (ACS).

  • Apixaban, in combination with standard antiplatelet drugs, was shown to increase the risk of major bleeding in patients with ACS (Acute Coronary Syndrome).
  • It has not been shown to have any clinical benefits.

• Hepatic impairment

  • You should avoid it in severe liver disease.
  • Moderate hepatic dysfunction patients should use it with caution because of the increased chance of major bleeding. There are not many safety data.

• Renal impairment

  • Patients with renal dysfunction should not use it.
  • The risk of systemic exposure to the drug increases in patients who have a CrCl less than 15 to 29, mL/minute.
  • It has also not been tested in clinical trials with patients who have a CrCl lower than 30 ml/minute.
  • Patients with non-valvular atrial fibrillation should have their dose reduced.
    • Serum creatinine should be 1.5 mg/dl and higher
    • Age 80 or older
    • Weight limit 60 kgs and less

• Valvular disease

  • Patients with severe rheumatic diseases, such as mitral Stenosis or prosthetic heart valves, should not use it.
  • Apixaban can be used as an alternative to warfarin in patients with atrial fibrillation, native aortic valve disease or mitral regurgitation, and a CHA2DS – VASc score of 2 and more.

Apixaban: Drug Interaction

Monitor:

• Renal function and complete blood counts before treatment initiation, as and when clinically indicated and at least annually thereafter.
• Monitor liver function
• Observe for evidence of bleeding, however, routine monitoring of the coagulation tests is not required.
• When switching to Vitamin K antagonists such as warfarin, check INR prior to each dose of apixaban (starting on the third day of concurrent therapy with warfarin)

How to administer Apixaban (Eliquis)?

• It is administered without regard to meals.
• The initial dose should be administered after 12 to 24 hours of hip or knee replacement surgery.
• The tablet can be crushed and mixed with 60 ml of water, 5% Dextrose solution, or applesauce and administered immediately if the patient can not swallow the whole tablet.
• Similarly, it can also be crushed and mixed with 60 ml of 5% dextrose water and administered via the nasogastric tube immediately after the preparation.
• When a suspension is made after crushing the tablet, the formulation remains stable for up to 4 hours in the water, D5W, apple juice, and applesauce.

Mechanism of action of Apixaban (Eliquis):

• Apixaban is selectively and reversibly inhibits clot-bound and free factor Xa. 
• This inhibits fibrin clot formation, and platelet activation.
• The inhibition of FactorXa stops the conversion of prothrombin into thrombin via the prothrombinase complicated that includes factor Va, calcium and phospholipids.
• Apixaban inhibits platelet activation as well as the conversion of fibrinogen into fibrin, since thrombin is necessary for activation of platelets.

It has beenThe beginning of action87% of the drug and a time of 3-4 hoursprotein-bound.

It is metabolized mainly via CYP3A4/5, but to a lesser degree via CYP1A2, CYP8 2C9 2C19 and 2J2 in liver to produce inactive metabolites.

It has been abioavailabilityAbout 50%half-life eliminationapproximately 12 hours. 

It takes approximately 12 hours to reach the destination.peak serum concentrationIt takes between 3 and 4 hours.

It isexcretedIn the urine and feces via direct excretion or biliary tract 

Apixaban Brand Names (International) and Price:

• Eliquis 5 mg tablets (each tablet Costs $9.42 in the US)
• Eliquis 2.5 mg tablets (each tablet Costs $9.42 in the US)

Apixaban Brand Names in Pakistan:

Eliquis (Pfizer) 2.5 mg and 5 mg price in Pakistan:

• Eliquis 2.5 mg costs 116.4 per tablet (a pack of 10 costs Rs. 1160)
• Eliquis 5 mg costs 121.21 per tablet (a  pack of 14 costs Rs. 1694)

Apiban 2.5 mg and 5 mg (Highnoon Pharmaceuticals):

• 2.5 mg costs Rs. 15 per tablet
• 5 mg costs Rs. 20 per tablet

Abaxil 2.5 mg and 5 mg (Saffron Pharmaceuticals) Zilero 2.5 mg and 5 mg (Pharmevo Pharmaceuticals)