Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation

Apixaban® (Apixaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

Apixaban is indicated 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.

Treatment of Deep Vein Thrombosis

Apixaban is indicated for the treatment of DVT.

Treatment of Pulmonary Embolism

Apixaban is indicated for the treatment of PE.

Reduction in the Risk of Recurrence of DVT and PE

Apixaban is indicated to reduce the risk of recurrent DVT and PE following initial therapy.

Apixaban is used to treat or prevent deep venous thrombosis, a condition in which harmful blood clots form in the blood vessels of the legs. These blood clots can travel to the lungs and can become lodged in the blood vessels of the lungs, causing a condition called pulmonary embolism. Apixaban is used for several days after hip or knee replacement surgery while you are unable to walk. It is during this time that blood clots are most likely to form.

Apixaban is also used to prevent stroke and blood clots in patients with certain heart rhythm problem (eg, nonvalvular atrial fibrillation).

Apixaban is a factor Xa inhibitor, an anticoagulant. It works by decreasing the clotting ability of the blood and helps preventing harmful clots from forming in the blood vessels.

Apixaban is available only with your doctor's prescription.

Apixaban can be taken with or without food.

If a dose is missed, the patient should take Apixaban immediately and continue with twice daily administration as before.

Recommended

Dosage: Prevention of VTE in Surgical Patients: Elective Hip or Knee Replacement Surgery: The recommended dose of Apixaban is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.

In patients undergoing hip replacement surgery, the recommended duration of treatment is 32 to 38 days.

In patients undergoing knee replacement surgery, the recommended duration of treatment is 10 to 14 days.

Prevention of Stroke and Systemic Embolism in Patients with AF: NVAF: The recommended dose of Apixaban is 5 mg taken orally twice daily.

Age, body weight, serum creatinine: In patients with at least 2 of the following characteristics, age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133 micromole/L), the recommended dose of Apixaban is 2.5 mg twice daily.

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

Prevention of Recurrent DVT and PE: The recommended dose of Apixaban is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE.

Renal Impairment: Prevention of VTE in Surgical Patients: Elective Hip or Knee Replacement Surgery: No dose adjustment is recommended in patients with mild, moderate or severe (creatinine clearance 15-29 mL/min) renal impairment. Because there is limited clinical experience in patients with creatinine clearance <15 mL/min and no data in patients undergoing dialysis, Apixaban is not recommended in these patients.

Prevention of Stroke and Systemic Embolism in Patients with AF: NVAF: No dose adjustment is recommended in patients with creatinine clearance 15 to 29 mL/min, except as described previously. Because there is no clinical experience in patients with creatinine clearance <15 mL/min, a dosing recommendation cannot be provided.

There are no data in patients undergoing dialysis, therefore, Apixaban is not recommended in these patients.

Treatment of VTE: No dose adjustment is necessary in patients with mild, moderate, or severe (creatinine clearance 15-29 mL/min) renal impairment. Because there is limited clinical experience in patients with creatinine clearance <15 mL/min and no data in patients undergoing dialysis, Apixaban is not recommended in these patients.

Hepatic Impairment: Apixaban may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment.

Apixaban is not recommended in patients with severe hepatic impairment.

Body Weight: Prevention of VTE in Surgical Patients: Elective Hip or Knee Replacement Surgery: No dose adjustment required.

Prevention of Stroke and Systemic Embolism in Patients with AF: NVAF: As mentioned previously in Recommended Dosage.

Treatment of VTE: No dose adjustment required.

Gender: No dose adjustment required.

Pediatric and Adolescents: The efficacy and safety of Apixaban in children below age 18 have not yet been established. No data are available.

Elderly: Prevention of VTE in Surgical Patients: Elective Hip or Knee Replacement Surgery: No dose adjustment required.

Prevention of Stroke and Systemic Embolism in Patients with AF: NVAF: As mentioned previously in Recommended Dosage.

Treatment of VTE: No dose adjustment required.

Converting From or To

Parenteral Anticoagulants:

Converting From or To Warfarin or Other Vitamin K Antagonists (VKA): When converting patients from warfarin or other VKA therapy to Apixaban, discontinue warfarin or other VKA therapy and start Apixaban when the international normalized ratio (INR) is below 2.0.

When converting from Apixaban to warfarin or other VKA therapy, continue Apixaban for 48 hours after the first dose of warfarin or other VKA therapy.

Surgery and Invasive Procedures: Apixaban 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 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. If surgery or invasive procedures cannot be delayed, exercise appropriate caution taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. In nonvalvular atrial fibrillation patients, bridging anticoagulation during the 24 to 48 hours after stopping Apixaban and prior to the intervention is not generally required. Apixaban should be restarted after the surgical or other procedure as soon as adequate hemostasis has been established.

Patients can continue taking Apixaban while being cardioverted.

Administration: For patients who are unable to swallow whole tablets, 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.

See also:
What is the most important information I should know about Apixaban?

Because Apixaban keeps your blood from coagulating (clotting) to prevent unwanted blood clots, this medicine can also make it easier for you to bleed, even from a minor injury such as a fall or a bump on the head. Avoid activities that may increase your risk of bleeding or injury. Contact your doctor or seek emergency medical attention if you have bleeding that will not stop.

Call your doctor at once if you have any signs of bleeding such as weakness, feeling like you might pass out, easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin, pink or brown urine, bloody or tarry stools, coughing up blood, joint pain or swelling, or heavy menstrual bleeding.

Tell any doctor or dentist who treats you that you are using Apixaban. If you need surgery or dental work, you may need to stop using the medicine for a short time.

Some drugs can raise or lower your blood levels of Apixaban, which may cause side effects or make Apixaban less effective. Many other drugs (including some over-the-counter medicines) can increase your risk of bleeding or life-threatening blood clots. It is very important to tell your doctor about all medicines you have recently used.

Do not stop taking Apixaban without first talking to your doctor. Stopping suddenly can increase your risk of blood clot or stroke.

Use Apixaban as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Apixaban comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Apixaban refilled.
• Take Apixaban by mouth with or without food.
• Taking Apixaban at the same time each day will help you remember to take it.
• Be sure to take Apixaban for the full course of treatment. If you do not, you may be at increased risk of developing blood clots. Keep taking it even if you feel well.
• If you miss a dose of Apixaban, take it as soon as possible on the same day you missed the dose then go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Apixaban.

Use: Labeled Indications

Deep vein thrombosis: Treatment of deep vein thrombosis (DVT); to reduce the risk of recurrent DVT following initial therapy

Nonvalvular atrial fibrillation: To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF)

Postoperative venous thromboprophylaxis following hip or knee replacement surgery: Prophylaxis of DVT, which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery

Pulmonary embolism: Treatment of PE; to reduce the risk of recurrent PE following initial therapy

Off Label Uses

Heparin-induced thrombocytopenia (treatment)

Data from several case reports and retrospective studies suggest that Apixaban may be used in the management of patients with heparin-induced thrombocytopenia (HIT).

Based on the American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia, Apixaban is an effective and recommended agent for heparin-induced thrombocytopenia complicated by thrombosis (HITT) or heparin-induced thrombocytopenia without thrombosis (isolated HIT).

Recurrent stroke/transient ischemic attacks (prevention)

Based on the American Heart Association/American Stroke Association (AHA/ASA) guidelines for the prevention of stroke in patients with stroke and transient ischemic attack, Apixaban 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 or anterior or apical wall-motion abnormalities with a left ventricular ejection fraction <40% who are intolerant to warfarin because of nonhemorrhagic adverse events.

See also:
What other drugs will affect Apixaban?

Inhibitors of CYP3A4 and P-gp: Co-administration of Apixaban with ketoconazole (400 mg once daily), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean Apixaban AUC and a 1.6-fold increase in mean Apixaban C_max.

The use of Apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp eg, azole-antimycotics (eg, ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (eg, ritonavir).

Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, (eg, diltiazem, naproxen, amiodarone, verapamil, quinidine) are expected to increase Apixaban plasma concentrations to a lesser extent. Diltiazem (360 mg once daily) eg, considered a moderate CYP3A4 and a weak P-gp inhibitor, led to a 1.4-fold increase in mean Apixaban AUC and a 1.3-fold increase in C_max. Naproxen (500 mg, single dose) an inhibitor of P-gp but not an inhibitor of CYP3A4, led to a 1.5-fold and 1.6-fold increase in mean Apixaban AUC and C_max, respectively. No dose adjustment for Apixaban is required when co-administered with less potent inhibitors of CYP3A4 and/or P-gp.

Inducers of CYP3A4 and P-gp: Co-administration of Apixaban with rifampicin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54% and 42% decrease in mean Apixaban AUC and C_max, respectively. The concomitant use of Apixaban with other strong CYP3A4 and P-gp inducers (eg, phenytoin, carbamazepine, phenobarbital or St. John's wort) may also lead to reduced Apixaban plasma concentrations. No dose adjustment for Apixaban is required during concomitant therapy with such agents; however, strong inducers of both CYP3A4 and P-gp should be co-administered with caution.

Anticoagulants, Platelets Aggregation Inhitors and Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated.

After combined administration of enoxaparin (40-mg single dose) with Apixaban (5-mg single dose), an additive effect on anti-Factor Xa activity was observed.

Pharmacokinetic or pharmacodynamic interactions were not evident when Apixaban was co-administered with ASA 325 mg once daily.

Apixaban co-administered with clopidogrel (75 mg once daily) or with the combination of clopidogrel 75 mg and ASA 162 mg once daily in phase 1 studies did not show a relevant increase in template bleeding time, or further inhibition of platelet aggregation, compared to administration of the antiplatelet agents without Apixaban. Increases in clotting tests (PT, INR and aPTT) were consistent with the effects of Apixaban alone.

Naproxen (500 mg), an inhibitor of P-gp, led to a 1.5- and 1.6-fold increase in mean Apixaban AUC and C_max, respectively. Corresponding increases in clotting tests were observed for Apixaban. No changes were observed in the effect of naproxen on arachidonic acid-induced platelet aggregation and no clinically relevant prolongation of bleeding time was observed after concomitant administration of Apixaban and naproxen.

Despite these findings, there may be individuals with a more pronounced pharmacodynamic response when anti-platelet agents are co-administered with Apixaban. Apixaban should be used with caution when co-administered with NSAIDs (including ASA) because these medicinal products typically increase the bleeding risk. A significant increase in bleeding risk was reported with the triple combination of Apixaban, acetylsalicylic acid and clopidogrel in a clinical study in patients with acute coronary syndrome.

Agents associated with serious bleeding are not recommended concomitantly with Apixaban eg, thrombolytic agents, GPIIb/IIIa receptor antagonists, thienopyridines (eg, clopidogrel), dipyridamole, dextran and sulfinpyrazone.

Other Concomitant Therapies: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when Apixaban was co-administered with atenolol or famotidine. Co-administration of Apixaban 10 mg with atenolol 100 mg did not have a clinically relevant effect on the pharmacokinetics of Apixaban. Following administration of the 2 medicinal products together, mean Apixaban AUC and C_max were 15% and 18%, respectively, lower than when administered alone. The administration of Apixaban 10 mg with famotidine 40 mg had no effect on Apixaban AUC or C_max.

Effect of Apixaban on Other Medicinal Products: In vitro Apixaban studies showed no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 >45 micromolar) and weak inhibitory effect on the activity of CYP2C19 (IC50 >20 micromolar) at concentrations that are significantly greater than peak plasma concentrations observed in patients. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at a concentration up to 20 micromolar. Therefore, Apixaban is not expected to alter the metabolic clearance of co-administered drugs that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp.

In studies conducted in healthy subjects, described as follows, Apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen or atenolol.

Digoxin: Co-administration of Apixaban (20 mg once daily) and digoxin (0.25 mg once daily), a P-gp substrate, did not affect digoxin AUC or C_max. Therefore, Apixaban does not inhibit P-gp mediated substrate transport.

Naproxen: Co-administration of single doses of Apixaban (10 mg) and naproxen (500 mg), a commonly used NSAID, did not have any effect on the naproxen AUC or C_max.

Atenolol: Co-administration of a single dose of Apixaban (10 mg) and atenolol (100 mg), a common β-blocker, did not alter the pharmacokinetics of atenolol.

Activated Charcoal: Administration of activated charcoal reduces Apixaban exposure.

Incompatibilities: Not applicable.

See also:
What are the possible side effects of Apixaban?

Clinical Experience: Prevention of VTE in Surgical Patients: Elective Hip or Knee Replacement Surgery: The safety of Apixaban has been evaluated in one phase II and three phase III studies including 5,924 patients exposed to Apixaban 2.5 mg twice daily undergoing major orthopedic surgery of the lower limbs (elective hip replacement or elective knee replacement) treated for up to 38 days.

In total, 11% of the patients treated with Apixaban 2.5 mg twice daily experienced adverse reactions. As with other anticoagulants, bleeding may occur during Apixaban therapy in the presence of associated risk factors such as organic lesions liable to bleed. Common adverse reactions were anemia, hemorrhage, contusion, and nausea. The overall incidences of adverse reactions of bleeding, anemia and abnormalities of transaminases (eg, alanine aminotransferase levels) were numerically lower in patients on Apixaban compared to enoxaparin in the phase II and phase III studies in elective hip and knee replacement surgery. The adverse reactions should be interpreted within the surgical setting.

As with any anticoagulant, the use of Apixaban may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which may result in posthemorrhagic anemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding.

Adverse reactions in the one phase II study and the three phase III studies are listed in Table 16 by system organ classification (MedDRA) and by frequency.

Prevention of Stroke and Systemic Embolism in Patients with AF: NVAF: The safety of Apixaban has been evaluated in the ARISTOTLE and AVERROES studies, including 11284 patients exposed to Apixaban 5 mg twice daily and 602 patients to 2.5 mg twice daily. The Apixaban exposures were >12 months for 9375 patients and >24 months for 3369 patients in the two studies. In ARISTOTLE, the mean duration of exposure was 89.2 weeks on Apixaban and 87.5 weeks on warfarin; total patient years for exposure was 15534 on Apixaban and 15184 on warfarin. In AVERROES, the mean duration of exposure was approximately 59 weeks in both treatment groups; total patient years for exposure was 3193 on Apixaban and 3150 on ASA.

The overall discontinuation rate due to adverse reactions was 1.8% for Apixaban and 2.6% for warfarin in the ARISTOTLE study, and was 1.5% for Apixaban and 1.3% for ASA in the AVERROES study. The overall incidence of adverse reactions related to bleeding was numerically lower in patients on Apixaban compared to warfarin in the ARISTOTLE study (24.3% vs 31.0%) and was similar in patients on Apixaban compared to ASA in the AVERROES study (9.6% vs 8.5%).

Adverse reactions in the ARISTOTLE and AVERROES studies are listed in Table 17 by system organ classification (MedDRA) and by frequency. The frequency assignments in Table 17 are primarily based on the frequencies observed in the ARISTOTLE study. The adverse reactions observed in the AVERROES study were consistent with those observed in the ARISTOTLE study.

Treatment of VTE: The safety of Apixaban has been evaluated in the AMPLIFY and AMPLIFY-EXT studies, including 2676 patients exposed to Apixaban 10 mg twice daily, 3359 patients exposed to Apixaban 5 mg twice daily, and 840 patients exposed to Apixaban 2.5 mg twice daily. The mean duration of exposure to Apixaban was 154 days and to enoxaparin/warfarin was 152 days in the AMPLIFY study. The mean duration of exposure to Apixaban was approximately 330 days and to placebo was 312 days in the AMPLIFY-EXT study.

In the AMPLIFY study, adverse reactions related to bleeding occurred in 417 (15.6%) of Apixaban-treated patients compared to 661 (24.6%) of enoxaparin/warfarin-treated patients. The discontinuation rate due to bleeding events was 0.7% in the Apixaban-treated patients compared to 1.7% in enoxaparin/warfarin-treated patients in the AMPLIFY study.

In the AMPLIFY-EXT study, adverse reactions related to bleeding occurred in 219 (13.3%) of Apixaban-treated patients compared to 72 (8.7%) of placebo-treated patients. The discontinuation rate due to bleeding events was approximately 1% in the Apixaban-treated patients compared to 0.4% in those patients in the placebo group in the AMPLIFY-EXT study.

Common adverse reactions (≥1%) were gingival bleeding, epistaxis, contusion, hematuria, hematoma, and menorrhagia.

Adverse reactions in the AMPLIFY and AMPLIFY-EXT studies are listed in Table 18 by system organ classification (MedDRA) and by frequency.

Apixaban, a selective inhibitor of the coagulation factor Xa (FXa), is 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. Its molecular formula is C₂₅H₂₅N₅O₄, which corresponds to a molecular weight of 459.5.

Apixaban is a white to pale yellow powder. At physiological pH (1.2-6.8), Apixaban does not ionize; its aqueous solubility across the physiological pH range is ~0.04 mg/mL.

Apixaban film-coated tablets are available for oral administration in strengths of 2.5 mg and 5 mg.

Excipients/Inactive Ingredients: Anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. Film-Coating: Lactose monohydrate, hypromellose, titanium dioxide, triacetin, yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets).