Tishk International University

Apixaban
SUBJECT
Therapeutics l
Prepared By:
Dyar Mudhafar Salman
4th Grade Group -A-

ASSIGNMENT SUBMITTED TO
Dr. Alan R. Muhammed
FACULTY OF PHARMACY
DEPARTMENT OF PHARMACOLOGY
TISHK INTERNATIONAL UNIVERSITY
ERBIL, KURDISTAN REGION, IRAQ
2020-2021

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Apixaban is an anticoagulant sold under the brand name Eliquis, Apixaban is an orally active direct inhibitor
of activated factor X (factor Xa) it binds to the active site of factor Xa, thereby preventing its ability to convert
prothrombin to thrombin. Apixaban has an oral bioavailability of 50% and prolonged absorption, resulting in
a half-life of 12 hours with repeat dosing, the drug is a substrate of the cytochrome P450 system and P-
glycoprotein and is excreted in the urine and feces. Grapefruit and its juice will increase serum levels of
apixaban. Drugs inhibiting both CYP3A4 and P-glycoprotein will increase the efficacy of apixaban, the
normal elimination half-life is around 12 hours, but this is prolonged in renal dysfunction.

Dosage Form
Tablet

Potency
1. 2.5mg
2. 5mg

Indication & Doses

1. Stroke Prophylaxis with Atrial Fibrillation: 5mg of Apixaban taken orally twice daily to prevent stroke
and systemic embolism in nonvalvular atrial fibrillation. If the patient has renal impairment you have to
follow these criteria:
• Mild-to-moderate: No dosage adjustment required
• Serum creatinine ≥1.5 mg/dL: Decrease dose to 2.5 mg twice daily if patient has 1 additional
characteristic of age ≥80 years or weight ≤60 kg.
• End-Stage Renal Disease (ESRD) maintained on hemodialysis: 5 mg twice daily; decrease dose to
2.5 mg twice daily if 1 additional characteristic of age ≥80 years or weight ≤60 kg is present.

2. Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE) Treatment:

• 10mg of Apixaban twice daily for 7 days, then maintenance 5mg twice daily for 3-6 months.
• To reduce risk for recurrent DVT or PE following initial 6 months treatment for DVT and/or PE
decrease dose to 2.5mg twice daily.

3. Postoperative Prophylaxis of DVT/PE: Indicated for following hip or knee replacement surgery:
• Initial: Give 2.5mg of apixaban orally 12-24hrs after surgery.
• Duration of therapy (hip replacement): 2.5mg of apixaban orally twice daily for 35 days.
• Duration of therapy (knee replacement): 2.5mg of apixaban orally twice daily for 10-14 days.

Dosage Modifications
Apixaban is a substrate for the cytochrome P450 system and the P-glycoprotein transporter. Drugs inhibiting
both CYP3A4 and P-glycoprotein (eg, ketoconazole) result in increased apixaban effect.
1. Coadministration with dual inhibitors of CYP3A4 and P-gp
• If taking >2.5mg of apixaban orally twice daily, decrease dose by 50%
• If taking 2.5 mg twice daily, avoid coadministration with strong dual inhibitors

2. Nonvalvular atrial fibrillation

• Decrease dose to 2.5mg of oral apixaban twice daily in patients with any 2 of the following
characteristics:
• Age ≥80 years
• Weight ≤60 kg
• Serum creatinine ≥1.5 mg/dL

3. Hepatic impairment
• Mild: No dosage adjustment required
• Moderate: Patients may have intrinsic coagulation abnormalities; data are limited and no
recommendations are available
• Severe: Not recommended

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Interactions
1. Dual inducers (carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone, Mitotane etc..) will
decrease the level or effect of apixaban by affecting hepatic/intestinal enzyme CYP3A4 metabolism.
Contraindicated. Reduces anticoagulant effect by decreasing apixaban systemic exposure.
2. Dual inhibitors of CYP3A4 and p-Gp (itraconazole, ketoconazole, voriconazole, verapamil, cobicistat,
dronedarone, erythromycin etc..) will increase the level or effect of apixaban by affecting hepatic/intestinal
enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If taking apixaban dose >2.5 mg BID,
decrease dose by 50% if coadministered with strong dual inhibitors of CYP3A4 and P-gp; if currently
taking apixaban 2.5 mg PO BID, avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp.

Side effects
1. Common or very common: Anaemia, haemorrhage, nausea, skin reactions.
2. Uncommon: CNS haemorrhage, hypotension, post procedural haematoma, thrombocytopenia, wound
complications

Contra-indications
1. Severe hypersensitivity (ie, anaphylactic reactions)
2. Active pathological bleeding
3. Risk factors for major bleeding: avoid in conditions with significant risk factors for major bleeding,
including current or recent gastrointestinal ulceration, malignant neoplasms at high risk of bleeding, recent
brain, spinal or ophthalmic surgery, recent intracranial hemorrhage, known or suspected esophageal
varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular
abnormalities.

Cautions
1. Anaesthesia with postoperative indwelling epidural catheter (risk of paralysis—monitor neurological signs
and wait 20–30 hours after apixaban dose before removing catheter and do not give next dose until at least
5 hours after catheter removal). prosthetic heart valve (efficacy not established). risk of bleeding.
2. Not recommended as an alternative to unfractionated heparin for the initial treatment of PE in patients who
present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
3. Not recommended for use in patients with triple-positive antiphospholipid syndrome (APS); for patients
with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and
anti–beta 2- glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of
recurrent thrombotic events compared with vitamin K antagonist therapy.
4. Avoid in pregnancy because Treatment is likely to increase the risk of hemorrhage during pregnancy and
delivery.

Pharmacology
Factor Xa inhibitor that inhibits platelet activation by selectively and reversibly blocking the active site of
factor Xa without requiring a cofactor (eg, antithrombin III) for activity. Inhibits free and clot-bound factor
Xa, and prothrombinase activity; no direct effect on platelet aggregation, but indirectly inhibits platelet
aggregation induced by thrombin. Blood coagulation cascade is dependent on the activation of factor X to
factor Xa via the intrinsic and extrinsic pathways, which play a central role in the blood coagulation cascade.

Pharmacokinetics
Absorption
• Bioavailability: Displays prolonged absorption Peak Plasma Concentration: 3-4 hr
Distribution
• Protein Bound: 87%
• Vdss: 21 L
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Metabolism
• Metabolized mainly by CYP3A4
• Metabolized with minor contributions from CYP1A2, 2C8, 2C9, 2C19 and 2J2
• Major sites of biotransformation: O-demethylation and hydroxylation at the 3-oxopirperidinyl moiety
• Metabolites: No active circulating metabolites Substrate of P-gp and BCRP
Elimination
• Half-life: 5-6 hr (dominant); 12 hr (apparent half-life with repeated dosing)
• Dialyzable: No
• Renal clearance: 27%
• Excretion: 25% in urine and feces as metabolites; renal excretion accounts for 27% of total clearance;
biliary and direct intestinal excretion contributes to elimination in feces.

Administration
May take with or without food
1. Missed dose
If 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. Do not double the dose to make up for a missed dose.
2. Unable to swallow whole tablets
5 mg and 2.5 mg tablets may be crushed and suspended in water, 5% dextrose in water (D5W), or apple
juice, or mixed with applesauce and promptly administered orally. Alternatively, tablets may be crushed and
suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube. Crushed tablets
are stable in water, D5W, apple juice, and applesauce for up to 4 hr.

References:
1. Joint Formulary Committee - British National Formulary (BNF) 78-Pharmaceutical Press (2019)
2. Whalen - Lippincott Illustrated Reviews Pharmacology
3. Roach’s Introductory Clinical Pharmacology by Susan M. Ford.
4. Cate Whittlesea, Karen Hodson - Clinical Pharmacy and Therapeutics-Elsevier (2018)
5. Caroline S. Zeind, Michael G. Carvalho (editors) - Applied therapeutics_ the clinical use of drugs-
Wolters Kluwer Health (2017)
6. National Institute for Health and Care Excellence (NICE Guidelines)