Apixaban

Before taking apixaban,

• tell your doctor and pharmacist if you are allergic to apixaban, any other medications, or any of the ingredients in apixaban tablets. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Teril); clarithromycin (Biaxin, in Prevpac); itraconazole (Onmel, Sporanox); ketoconazole (Nizoral); phenytoin (Dilantin, Phenytek); rifampin (Rifadin, Rimactane, in Rifadin, in Rifater); ritonavir (Norvir, in Kaletra); selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), fluoxetine (Prozac, Sarafem, Selfemra, in Symbyax), fluvoxamine (Luvox), paroxetine (Brisdelle, Paxil, Pexeva), and sertraline (Zoloft); and serotonin and norepinephrine reuptake inhibitors (SNRIs) such as duloxetine (Cymbalta), desvenlafaxine (Khedezla, Pristiq), milnacipran (Fetzima, Savella), and venlafaxine (Effexor). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with apixaban, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor what herbal products you are taking, especially St. John's wort.
• you should know that apixaban may interact with certain medications that may be used to treat you if you have a stroke or other medical emergency. In case of an emergency, you or a family member should tell the doctor or emergency room staff who treat you that you are taking apixaban.
• tell your doctor if you have an artificial heart valve or if you have heavy bleeding anywhere in your body that cannot be stopped. Your doctor will probably tell you not to take apixaban.
• tell your doctor if you have or have ever had any type of bleeding problem, or kidney or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking apixaban, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking apixaban. Your doctor may tell you to stop taking apixaban before the surgery or procedure. If you need to stop taking apixaban because you are having surgery, your doctor may prescribe a different medication to prevent blood clots during this time. Your doctor will tell you when you should start taking apixaban again after your surgery. Follow these directions carefully.
• Call your doctor right away if you fall or injure yourself, especially if you hit your head. Your doctor may need to check you.

Unless your doctor tells you otherwise, continue your normal diet.

• Eliquis^®

Serious Side Effects of Eliquis

Tell your doctor immediately if you experience any of the symptoms listed in the Eliquis Warnings section above, or the following serious side effects:

• Easy bruising
• Unusual bleeding or bleeding that won't stop, including nosebleeds and bleeding gums
• Heavy menstrual periods
• Pink, brown, or red urine
• Black or bloody stools
• Coughing up blood, or vomit that looks like coffee grounds
• Trouble breathing or wheezing
• Severe headache
• Dizziness or feeling like you might pass out
• Severe weakness
• Rash
• Swelling or joint pain
• Chest pain or tightness
• Signs of anaphylaxis, which may include hives, difficulty breathing, or swelling of the face, lips, tongue, or throat

• The usual dose in nonvalvular atrial fibrillation is 5 mg by mouth twice daily. For individuals 80 years or older, weighing less than or equal to 60 kg, or with reduced kidney function, the usual dose is 2.5 mg twice daily.
• The recommended dose for treating DVT or pulmonary embolism is 10 mg twice daily for the first 7 days and then 5 mg twice daily. After six months of treatment, the dose may be reduced to 2.5 mg daily for prevention of DVT or pulmonary embolism.
• When apixaban is used to prevent the risk of DVT after hip or knee replacement surgery, the suggested dose is 2.5 mg daily beginning 12 to 24 hours after the surgery is completed.

Dosage Forms & Strengths

tablet

• 2.5mg
• 5mg

Stroke Prophylaxis with Atrial Fibrillation

Indicated to reduce risk of stroke and systemic embolism associated with nonvalvular atrial fibrillation

5 mg PO BID

Postoperative Prophylaxis of DVT/PE

Indicated following hip or knee replacement surgery

Initial: Give 2.5 mg PO 12-24 hr after surgery

Duration of therapy (hip replacement): 2.5 mg PO BID for 35 days

Duration of therapy (knee replacement): 2.5 mg PO BID for 12 days

Renal impairment, including with ESRD on dialysis

• Deep Vein Thrombosis: No dose adjustment recommended; clinical efficacy and safety studies did not enroll patients with ESRD on dialysis or patients with a CrCl <15 mL/min; dosing recommendations are based on pharmacokinetic and pharmacodynamic (anti-FXa activity) data in study subjects with ESRD maintained on dialysis

DVT or PE Treatment

Indicated for treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE)

10 mg PO BID x 7 days, then 5 mg BID

Reduce risk for recurrent DVT or PE

• Indicated to reduce the risk of recurrent DVT and PE following initial 6 months treatment for DVT and/or PE
• 2.5 mg PO BID

Renal impairment, including with ESRD

• No dose adjustment recommended; clinical efficacy and safety studies did not enroll patients with ESRD on dialysis or patients with a CrCl <15 mL/min; dosing recommendations are based on pharmacokinetic and pharmacodynamic (anti-FXa activity) data in study subjects with ESRD maintained on dialysis

Dosage Modifications

Coadministration with dual inhibitors of CYP3A4 and P-gp

• If taking >2.5 PO BID, decrease dose by 50%
• If taking 2.5 mg BID, avoid coadministration with strong dual inhibitors

Nonvalvular atrial fibrillation

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

Renal impairment (nonvalvular atrial fibrillation)

• Mild-to-moderate: No dosage adjustment required
• Serum creatinine ≥1.5 mg/dL: Decrease dose to 2.5 mg BID if patient has 1 additional characteristic of age ≥80 years or weight ≤60 kg
• ESRD maintained on hemodialysis: 5 mg BID; decrease dose to 2.5 mg BID if 1 additional characteristic of age ≥80 years or weight ≤60 kg is present

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

Dosing Considerations

Switching between apixaban and anticoagulants other than warfarin: Discontinue one being taken, and begin the other at the next scheduled dose

Switching from warfarin to apixaban: Discontinue warfarin and initiate apixaban when INR <2.0

Switching from apixaban to warfarin

• Apixaban affects INR, so measurements during coadministration with warfarin may not determine appropriate warfarin dose
• If continuous anticoagulation is necessary, discontinue apixaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of apixaban would have been taken
• Discontinue parenteral anticoagulant when INR reaches an acceptable level

Surgery/procedures

• Discontinue at least 48 hr before elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding
• Discontinue at least 24 hr before elective surgery or invasive procedures with a low risk of unacceptable or where the bleeding would be noncritical in location and easily controlled

Administration

May take with or without food

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

For patients who are 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

Safety and efficacy not established

Apixaban is part of the drug class:

• Direct factor Xa inhibitors

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is unknown whether apixaban or its metabolites are excreted in human milk.

Women should be instructed either to stop breastfeeding or to stop apixaban therapy, taking into account the importance of the drug to the mother.

Metabolized by CYP3A4/5, and to a lesser extent by CYP isoenzymes 1A2, 2C8, 2C9, 2C19, and 2J2.1 15

Does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 3A4/5, or 2C19 nor induce CYP isoenzymes 1A2, 2B6, or 3A4/5.1 15 16

Substrate of the efflux transporter P-glycoprotein, but does not substantially inhibit P-glycoprotein.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP3A4/5: Although pharmacokinetic interactions are possible, potential may be low because of apixaban’s multiple routes of elimination.8 15 35 77

Pharmacokinetic interactions unlikely with drugs metabolized by major CYP isoenzymes.1 15 16

Drugs Affecting P-glycoprotein Transport

Inhibitors or inducers of P-glycoprotein: Potential pharmacokinetic interaction.1

Drugs Affecting P-glycoprotein and CYP3A4

Combined P-glycoprotein and CYP3A4 inhibitors: Possible increased apixaban exposure, which may increase risk of bleeding.1 Reduce dosage if used concomitantly with a potent dual inhibitor of P-glycoprotein and CYP3A4; avoid use if patient already receiving reduced dosage.1 (See Dosage under Dosage and Administration and also see Specific Drugs under Interactions.)

Combined P-glycoprotein and CYP3A4 inducers: Possible decreased apixaban exposure, which may increase risk of stroke.1 Avoid concomitant use with potent dual inducers of P-glycoprotein and CYP3A4.1

Drugs Affecting Hemostasis

Potential increased risk of hemorrhage.1 8 Promptly evaluate any manifestations of bleeding.1

Specific Drugs

• If you have an allergy to apixaban or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Active bleeding or liver problems.
• If you have had a heart valve replaced.
• If you are taking any of these drugs: Carbamazepine, clarithromycin, itraconazole, ketoconazole, phenytoin, rifampin, ritonavir, St. John's wort, telithromycin, or voriconazole.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with apixaban.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take apixaban. This includes your doctors, nurses, pharmacists, and dentists. This medicine may need to be stopped before certain types of surgery as your doctor has told you. If this medicine is stopped, your doctor will tell you when to start taking apixaban again after your surgery or procedure.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Do not run out of this medicine.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• Very bad and sometimes deadly bleeding problems have happened with apixaban. Talk with the doctor.
• If you fall or hurt yourself, or if you hit your head, call your doctor right away. Talk with your doctor even if you feel fine.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.

• Anticoagulant
• Anticoagulant, Factor Xa Inhibitor
• Direct Oral Anticoagulant (DOAC)

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 in patients who are intolerant to warfarin because of nonhemorrhagic adverse events, in patients with an acute MI complicated by left ventricular mural thrombus formation or anterior or apical wall-motion abnormalities with a left ejection fraction <40% for the prevention of recurrent stroke or transient ischemic attacks.

US labeling: Severe hypersensitivity reaction (ie, anaphylaxis) to apixaban or any component of the formulation; active pathological bleeding

Canadian labeling: Hypersensitivity to apixaban or any component of the formulation; clinically-significant active bleeding (including gastrointestinal bleeding); lesions or conditions at increased risk of clinically-significant bleeding (eg, cerebral infarct [ischemic or hemorrhagic], active peptic ulcer disease with recent bleeding; patients with spontaneous or acquired impairment of hemostasis); hepatic disease associated with coagulopathy and clinically-relevant bleeding risk; concomitant systemic treatment with agents that are strong inhibitors of both CYP3A4 and P-glycoprotein (P-gp); concomitant treatment with any other anticoagulant including unfractionated heparin (except at doses used to maintain patency of central venous or arterial catheter), low molecular weight heparins, heparin derivatives (eg, fondaparinux), and oral anticoagulants including warfarin, dabigatran, rivaroxaban except when transitioning to or from apixaban therapy

The International Society on Thrombosis and Haemostasis (ISTH) 2016 guideline suggests avoiding the use of apixaban (and other direct oral anticoagulants) in patients with a BMI >40 kg/m2 or weight >120 kg due to the lack of clinical data in this population. If used in a patient with a BMI >40 kg/m2 or weight >120 kg, ISTH suggests measuring peak and trough levels using an antifactor Xa assay or mass spectrometry. If drug level is below the expected range, ISTH suggests changing to a vitamin K antagonist rather than adjusting the dose of apixaban (ISTH [Martin 2016]).

Premature discontinuation of any oral anticoagulant, including apixaban, increases the risk of thrombotic events. If anticoagulation with apixaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

Epidural or spinal hematomas may occur in patients treated with apixaban who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; a history of spinal deformity or spinal surgery; optimal timing between the administration of apixaban and neuraxial procedures is not known.

Monitor patients frequently for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated.

Renal function prior to initiation, when clinically indicated, and at least annually in all patients (AHA/ACC/HRS [January, 2014]), hepatic function; signs of bleeding. Routine monitoring of coagulation tests is not required. Although not recommended to assess effectiveness, the prothrombin time (PT), INR, and aPTT are prolonged with apixaban. Anti-FXa assay may be helpful (plasma concentrations and anti-FXa activity exhibit linear relationship) in guiding clinical decisions.

When converting from apixaban to a vitamin K antagonist (VKA), it has been recommended to perform INR testing just prior to each dose of apixaban beginning on day 3 of concurrent therapy with the VKA (Eliquis Canadian product labeling 2016).

• May be taken with or without food.
• Tablets may be crushed and mixed with water or apple juice/sauce to make swallowing easier. Swallow mixture straight away and do not save for later use.
• Apixaban is usually dosed twice daily. Check with your doctor what dosage is recommended for you.
• Tell all healthcare providers that you are taking Apixaban. Apixaban may need to be temporarily discontinued at least 48 hours prior to surgery that carries a moderate-to-high risk of unacceptable or clinically significant bleeding; 24 hours before surgery with a low risk of bleeding or if bleeding likely to be noncritical. Bridging therapy is not usually required and apixaban should be re-started once the risk of bleeding post-surgery has returned to normal.
• Apixaban may also increase your risk of bleeding from a minor fall or bump on the head. Contact your doctor if you experience an injury or have bleeding that will not stop.
• Your doctor may require you to undertake extra monitoring when switching to or from apixaban.
• Do not stop taking apixaban suddenly. Your doctor will advise you on how to discontinue apixaban when or if you no longer require it.

Animal studies did not show an increased risk of fetal malformations or toxicity, and no maternal or fetal deaths were attributed to bleeding. Increased maternal bleeding was seen at concentrations higher than the usual human exposure. There are no controlled data in human pregnancy. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Use is not recommended. (AU, UK) This drug should be used during pregnancy only if the benefit outweighs the risk to the mother and fetus. (US) AU TGA pregnancy category: C US FDA pregnancy category: B Comments: -Treatment can cause placental hemorrhage and subsequent fetal loss. -Treatment increases the risk of hemorrhage during pregnancy and delivery.