Apixabanum

Uses

Apixabanum is a factor Xa inhibitor used:

• To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• For the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery
• For the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following initial therapy

Apixabanum is also used to associated treatment for these conditions: Deep Vein Thrombosis, Deep vein thrombosis recurrent, Pulmonary Embolism, Recurrent pulmonary embolism, Stroke, Systemic Embolism

How Apixabanum works

Apixabanum selectively inhibits factor Xa in its free and bound forms, independant of antithrombin III. Apixabanum also inhibits prothrominase. These effects prevent the formation of a thrombus.

Dosage

Apixabanum dosage

Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation:

• The recommended dose: 5 mg orally twice daily.
• In patients with at least 2 of the following characteristics: age greater than or equal to 80 years, body weight less than or equal to 60 kg, or serum creatinine greater than or equal to 1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily.

Prophylaxis of DVT following hip or knee replacement surgery: The recommended dose is 2.5 mg orally twice daily.

Treatment of DVT and PE: The recommended dose is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily.

Reduction in the risk of recurrent DVT and PE following initial therapy: The recommended dose is 2.5 mg taken orally twice daily.

Side Effects

Apixabanum can cause a skin rash or severe allergic reaction.

Toxicity

Animal studies have shown an increased risk of maternal bleeding during pregnancy but no increase in fetal malformations or fetal or maternal deaths. It is unknown if this animal data also translates to humans so apixaban should only be used in pregnancy if the benefits outweigh the risks. It is not know whether apixaban is safe and effective in labor and during birth, though animal studies have shown an increased rate of maternal bleeding. Animal studies in rats show apixaban excreted in milk, though it is not know if this also applies to humans. Nursing mothers should either stop breastfeeding or stop taking apixaban depending on the risk and benefit of each option. Studies to determine safety and effectiveness in pediatric patients have yet to be performed. Studies that involved geriatric patients (at least 75 years old) saw no difference in safety or effectiveness compared to younger patients, though geriatric patients at an especially advanced age may be more susceptible to adverse effects. Dosage adjustments for patients with end stage renal disease(ESRD) are based on estimates of pharmacokinetic principles and not clinical study. Patients with ESRD may experience pharmacodynamics similar to those seen in well controlled studies but it may not lead to the same clinical effects. Dosage adjustments are not necessary in mild hepatic impairment. In moderate hepatic impairment patients may already experience abnormalities in coagulation and so no dose recommendations are possible. Apixabanum is not recommended for patients with severe hepatic impairment.

Precaution

Apixabanum can cause serious, potentially fatal, bleeding. Promptly evaluate signs and symptoms of blood loss. An agent to reverse the anti-factor Xa activity of apixaban is available.

Interaction

Combined P-gp and strong CYP3A4 inhibitors increase blood levels of apixaban. Reduce Apixabanum dose or avoid coadministration.

Simultaneous use of combined P-gp and strong CYP3A4 inducers reduces blood levels of apixaban: Avoid concomitant use

Food Interaction

• Avoid grapefruit products.
• Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.
• Avoid St. John's Wort. St. John's Wort will decrease levels of this medication.
• Take with or without food.

Apixabanum Drug Interaction

Major: aspirin, aspirinModerate: omega-3 polyunsaturated fatty acidsUnknown: ubiquinone, rosuvastatin, insulin glargine, furosemide, atorvastatin, pregabalin, metoprolol, metoprolol, polyethylene glycol 3350, acetaminophen, tiotropium, budesonide / formoterol, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Apixabanum Disease Interaction

Major: bleeding, hepatic impairment, valvular heart disease

Volume of Distribution

Approximately 21L.

Elimination Route

Apixabanum is approximately 50% bioavailable though other studies report 43-46% oral bioavailability.

Half Life

12.7±8.55h.

Clearance

3.3L/h though other studies report 4876mL/h.

Elimination Route

56% of an orally administered dose is recovered in the feces and 24.5-28.8% of the dose is recovered in the urine. 83-88% of the dose recovered in the urine was the unchanged parent compound.

Pregnancy & Breastfeeding use

Pregnancy Category B. There are no adequate and well-controlled studies of Apixabanum in pregnant women. Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. Apixabanum 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).

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 Apixabanum therapy, taking into account the importance of the drug to the mother.

Contraindication

Active pathological bleeding. Severe hypersensitivity to Apixabanum

Acute Overdose

Overdose of Apixabanum increases the risk of bleeding. 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. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion. An agent to reverse the anti-factor Xa activity of apixaban is available.

Interaction with other Medicine

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Innovators Monograph

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