APIXABEK

Apixaban is an oral, direct, and highly selective factor Xa (FXa) inhibitor of both free and bound FXa, as well as prothrombinase, independent of antithrombin III for the prevention and treatment of thromboembolic diseases Label, 2.

It is marketed under the name Eliquis Label, 3.

Apixaban was approved by the FDA on December 28, 2012 3.

Apixaban is indicated for reducing the risk of stroke and systemic embolism in patients who have nonvalvular atrial fibrillation, prophylaxis of deep vein thrombosis(DVT) leading to pulmonary embolism(PE) in patients after a hip or knee replacement surgery, and treatment of DVT and PE to reduce the risk of recurrence Label, 1, 2.

Apixaban selectively inhibits factor

Xa in its free and bound forms, independant of antithrombin III Label.

Apixaban also inhibits prothrominase

These effects prevent the formation of a thrombus Label.

Apixaban is approximately 50% bioavailable Label though other studies report 43-46% oral bioavailability 1.

Approximately 21 L Label.

50% of the Oral administered dose is excreted as the unchanged parent compound, however 25% of the dose is excreted as O-demethyl apixaban sulfate Label, 1.

All apixaban metabolites account for approximately 32% of the excreted dose though the structure of all metabolites are not well defined 1.

Apixaban is mainly metabolized by cytochrome p450(CYP)3A4 and to a lesser extent by CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2J2 Label.

Hover over products below to view reaction partners Apixaban Apixaban M2 metabolite.

56% of an Oral administered dose is recovered in the feces and 24.5-28.8% of the dose is recovered in the urine Label, 1, 2. 83-88% of the dose recovered in the urine was the unchanged parent compound 1.

L/h Label though other studies report 4876 mL/h 1.

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Animal studies have shown an increased risk of maternal bleeding during pregnancy but no increase in fetal malformations or fetal or maternal deaths Label.

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 Label.

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 Label.

Animal studies in rats show apixaban excreted in milk, though it is not know if this also applies to humans Label.

Nursing mothers should either stop breastfeeding or stop taking apixaban depending on the risk and benefit of each option Label.

Studies to determine safety and effectiveness in pediatric patients have yet to be performed Label.

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 Label.

Dosage adjustments for patients with end stage renal disease(ESRD) are based on estimates of pharmacokinetic principles and not clinical study Label.

Patients with

ESRD may experience pharmacodynamics similar to those seen in well controlled studies but it may not lead to the same clinical effects Label.

Dosage adjustments are not necessary in mild hepatic impairment Label.

In moderate hepatic impairment patients may already experience abnormalities in coagulation and so no dose recommendations are possible Label.

Apixaban is not recommended for patients with severe hepatic impairment Label.

• Active pathological bleeding.

• Severe hypersensitivity reaction to apixaban (e.g., anaphylactic reactions) Active pathological bleeding Severe hypersensitivity to apixaban.

& ADMINISTRATION Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation: The recommended dose is 5 mg orally twice daily.

In patients with at least 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.

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. 2.1 Recommended Dose Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation The recommended dose of apixaban tablets for most patients is 5 mg taken orally twice daily.

• age greater than or equal to 80 years.

• body weight less than or equal to 60 kg.

• serum creatinine greater than or equal to 1.5 mg/dL Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery The recommended dose of apixaban tablets is 2.5 mg taken orally twice daily.

The initial dose should be taken to 24 hours after surgery.

• In patients undergoing hip replacement surgery, the recommended duration of treatment is 35 days.

• In patients undergoing knee replacement surgery, the recommended duration of treatment is 12 days.

The recommended dose of apixaban tablets is 10 mg taken orally twice daily for the first 7 days of therapy.

After 7 days, the recommended dose is 5 mg taken orally twice daily.

Reduction in the Risk of Recurrence of DVT and PE The recommended dose of apixaban tablets is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE. 2.2 Missed Dose If a dose of apixaban tablets 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. 2.3 Temporary Interruption for Surgery and Other Interventions Apixaban tablets 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.

Apixaban tablets 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.

Bridging anticoagulation during the to 48 hours after stopping apixaban tablets and prior to the intervention is not generally required.

Apixaban tablets should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established. 2.4 Converting from or to apixaban Switching from warfarin to apixaban: Warfarin should be discontinued and apixaban started when the international normalized ratio (INR) is below 2.0.

Switching from apixaban to warfarin: apixaban affects INR, so that initial INR measurements during the transition to warfarin may not be useful for determining the appropriate dose of warfarin.

One approach is to discontinue apixaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of apixaban would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.

Switching from apixaban to anticoagulants other than warfarin (oral or parenteral): Discontinue apixaban and begin taking the new anticoagulant other than warfarin at the usual time of the next dose of apixaban.

Switching from anticoagulants other than warfarin (oral or parenteral) to apixaban: Discontinue the anticoagulant other than warfarin and begin taking apixaban at the usual time of the next dose of the anticoagulant other than warfarin. 2.5 Combined P-gp and Strong CYP3A4 Inhibitors For patients receiving apixaban tablets doses of 5 mg or 10 mg twice daily, reduce the dose by 50% when apixaban tablet is coadministered with drugs that are combined P-glycoprotein (P-gp) and strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, itraconazole, ritonavir) .

In patients already taking 2.5 mg twice daily, avoid coadministration of apixaban tablets with combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitors. 2.6 Administration Options For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg apixaban 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, apixaban tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube.

Crushed apixaban tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours.

Apixaban tablets 2.5mg and 5mg are available as below. 2.5mg, yellow, round, film coated biconvex tablets debossed with "C31" on one side and plain on the other side.

NDC 14445-149-60 Bottles of 60 NDC 14445-149-18 Bottles of 180 NDC 14445-149-05 Bottles of 500 NDC 14445-149-14 Unit-Dose Blister Package 10x 14's 5 mg, pink, oval, film coated biconvex tablets debossed with "C32" on one side and plain on the other side.

NDC 14445-150-60 Bottles of 60 NDC 14445-150-18 Bottles of 180 NDC 14445-150-05 Bottles of 500 NDC 14445-150-10 Unit-Dose Blister Package 10x 10's 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) .

The limited available data on apixaban tablets use in pregnant women are insufficient to inform drug-associated risks of major birth defects, miscarriage, or adverse developmental outcomes.

Treatment may increase the risk of bleeding during pregnancy and delivery.

In animal reproduction studies, no adverse developmental effects were seen when apixaban was administered to rats (orally), rabbits (intravenously) and mice (orally) during organogenesis at unbound apixaban exposure levels up to and 19 times, respectively, the human exposure based on area under plasma-concentration time curve (AUC) at the Maximum Recommended Human Dose (MRHD) of 5 mg twice daily.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Disease-associated maternal and/or embryo/fetal risk Pregnancy confers an increased risk of thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions.

Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy.

Fetal/Neonatal adverse reactions Use of anticoagulants, including apixaban, may increase the risk of bleeding in the fetus and neonate.

Labor or delivery

All patients receiving anticoagulants, including pregnant women, are at risk for bleeding.

Apixaban tablets use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas.

Consider use of a shorter acting anticoagulant as delivery approaches.

No developmental toxicities were observed when apixaban was administered during organogenesis to rats (orally), rabbits (intravenously) and mice (orally) at unbound apixaban exposure levels 4, 1, and 19 times, respectively, the human exposures at the MRHD.

There was no evidence of fetal bleeding, although conceptus exposure was confirmed in rats and rabbits.

Oral administration of apixaban to rat dams from gestation day 6 through lactation day at maternal unbound apixaban exposures ranging from 1.4 to 5 times the human exposures at the MRHD was not associated with reduced maternal mortality or reduced conceptus/neonatal viability, although increased incidences of peri-vaginal bleeding were observed in dams at all doses.

There was no evidence of neonatal bleeding.

Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including apixaban should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

Safety and effectiveness in pediatric patients have not been established.

Of the total subjects in the ARISTOTLE and AVERROES clinical studies, >69% were 65 years of age and older, and >31% were 75 years of age and older.

In the

ADVANCE-1, ADVANCE-2, and ADVANCE-3 clinical studies, 50% of subjects were 65 years of age and older, while 16% were 75 years of age and older.

In the AMPLIFY and

AMPLIFY-EXT clinical studies, >32% of subjects were 65 years of age and older and >13% were 75 years of age and older.

No clinically significant differences in safety or effectiveness were observed when comparing subjects in different age groups.