Drug Safety-related Labeling Changes (SrLC)

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ELIQUIS (NDA-202155)

(APIXABAN)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/17/2025 (SUPPL-39)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Bleeding

Additions and/or revisions underlined:

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Reversal of Anticoagulant Effect

A specific reversal agent (andexanet alfa) antagonizing the pharmacodynamic effect of apixaban is available for adults. However, its safety and efficacy have not been established in pediatric patients (refer to the USPI of andexanet alfa). The pharmacodynamic effect of ELIQUIS can be expected to persist for at least 24 hours after the last dose, i.e., for about two drug half-lives. Prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa may be considered, but have not been evaluated in clinical studies [see Clinical Pharmacology (12.2)]. When PCCs are used, monitoring for the anticoagulation effect of apixaban using a clotting test (PT, INR, or aPTT) or anti-factor Xa (FXa) activity is not useful and is not recommended. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration [see Overdosage (10)].

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5.3 Spinal/Epidural Anesthesia or Puncture

Additions and/or revisions underlined:

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No data are available on the timing of the placement or removal of neuraxial catheters in pediatric patients while on ELIQUIS. In such cases, discontinue ELIQUIS and consider a short acting parenteral anticoagulant.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

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Pediatric Patients

Treatment of Venous Thromboembolism (VTE) and Reduction in the Risk of Recurrent VTE in Pediatric Patients

The safety assessment of ELIQUIS is based on data from CV185325, a phase 3 study in 225 patients from birth and older. Patients were randomized 2:1 to receive body weight-adjusted doses of an age-appropriate formulation of ELIQUIS or standard of care. The standard of care treatments included unfractionated heparin (UFH), low molecular weight heparin (LMWH), or vitamin K antagonist (VKA).

Overall, the safety profile of ELIQUIS in pediatric patients from birth and older was generally similar to that in adults and consistent across different pediatric age groups. In pediatric patients, excessive menstrual bleeding occurred in 17 (11%) patients in the ELIQUIS group and 3 (4%) patients in the standard of care group. Epistaxis occurred in 24 (16%) patients in the ELIQUIS group and 14 (19%) patients in the standard of care group.

Bleeding results from Study CV185325 in pediatric patients with VTE are summarized in Table 10.

Please refer to label to view Table 10.

Non-bleeding adverse reactions occurring in greater than or equal to 10% of patients in study CV185325 are listed in Table 11.

Please refer to label to view table 11.

7 Drug Interactions

 7.1 Combined P-gp and Strong CYP3A4 Inhibitors

Additions and/or revisions underlined:

Concomitant administration of combined P-gp and strong CYP3A4 inhibitors has not been studied in pediatric patients.

Apixaban is a substrate of both CYP3A4 and P-gp. Concomitant use with drugs that are combined P-gp and strong CYP3A4 inhibitors increases exposure to apixaban [see Clinical Pharmacology (12.3)] which increases the risk for bleeding.

…

7.2 Combined P-gp and Strong CYP3A4 Inducers

Additions and/or revisions underlined:

…

Apixaban is a substrate of both CYP3A4 and P-gp. Concomitant use with drugs that are combined P-gp and strong CYP3A4 inducers decreases exposure to apixaban [see Clinical Pharmacology (12.3)] which increases the risk for stroke and other thromboembolic events.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of ELIQUIS for the treatment of VTE and the reduction in the risk of recurrent VTE have been established in pediatric patients aged birth and older. Use of ELIQUIS for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety, and efficacy data in pediatric patients. These studies included a randomized, active controlled, open label, multi-center study of ELIQUIS [see Adverse Reactions (6.1) and Clinical Studies (14.4)].

8.6 Renal Impairment

Additions and/or revisions underlined:

…

Treatment of Venous Thromboembolism (VTE) and Reduction in the Risk of Recurrent VTE in Pediatric Patients

In pediatric patients equal to or greater than 2 years of age, ELIQUIS is not recommended in patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 body surface area (BSA).

In patients less than 2 years of age, ELIQUIS is not recommended in patients with inadequate renal function defined by sex and postnatal age as used in the pediatric VTE trial for ELIQUIS (see Table 12 below).

To estimate GFR, the pediatric VTE trial for ELIQUIS used the updated Schwartz formula, eGFR (ml/min/1.73m2) = 0.413 * height (cm)/serum creatinine (mg/dL) for serum creatinine measured by an enzymatic creatinine method calibrated to be traceable to isotope dilution mass spectrometry (IDMS).

Table 12:       Inadequate renal function by sex and post-nasal age in pediatric patients

<2 years of age as defined in the pediatric VTE trial for ELIQUIS

Please refer to label to view Table 12.

8.7 Hepatic Impairment

Additions and/or revisions underlined:

…

ELIQUIS has not been studied in pediatric patients with hepatic impairment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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Pediatric Patients

Advise the caregiver or the patient of the following:

• To always give this medicine exactly as the child’s physician or pharmacist has instructed them.

• The importance of keeping scheduled physician’s visits. ELIQUIS dose is based on body weight and the dose may need to be adjusted as the child’s weight changes. This ensures that the child receives the correct dose of ELIQUIS. The physician may adjust the child’s dose when needed. The caregiver should be advised not to adjust the dose themselves.

• What to do if the child vomits or spits up. If a child vomits or spits up within 30 minutes after taking ELIQUIS, repeat the dose. If a child vomits or spits up more than 30 minutes after taking ELIQUIS, do not repeat the dose. Continue to give the next ELIQUIS dose at the next scheduled time. The caregiver should contact the physician if the child repeatedly vomits or spits up after taking ELIQUIS.

  MEDICATION GUIDE

  Extensive additions and/or revisions, please refer to label for complete information.

10/12/2021 (SUPPL-34)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

Before you take ELIQUIS, tell your doctor if you:

•           have kidney or liver problems

•           have antiphospholipid syndrome

•           have any other medical condition

•           have ever had bleeding problems

•           are pregnant or plan to become pregnant. It is not known if ELIQUIS will harm your unborn baby.

Females who are able to become pregnant: Talk with your healthcare provider about pregnancy planning during treatment with ELIQUIS. Talk with your healthcare provider about your risk of severe uterine bleeding if you are treated with blood thinner medicines, including ELIQUIS.

04/20/2021 (SUPPL-32)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(Newly Added Subsection)

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 ELIQUIS should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

11/26/2019 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Bleeding

(Additions and/or revisions underlined)

ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding.

Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti- inflammatory drugs (NSAIDs).

Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue ELIQUIS in patients with active pathological hemorrhage.

Reversal of Anticoagulant Effect

An agent to reverse the anti-factor Xa activity of apixaban is available. The pharmacodynamic effect of ELIQUIS can be expected to persist for at least 24 hours after the last dose, i.e., for about two drug half-lives. Prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa may be considered, but have not been evaluated in clinical studies. When PCCs are used, monitoring for the anticoagulation effect of apixaban using a clotting test (PT, INR, or aPTT) or anti-factor Xa (FXa) activity is not useful and is not recommended. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration.

Hemodialysis does not appear to have a substantial impact on apixaban exposure. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is no experience with systemic hemostatics (desmopressin) in individuals receiving ELIQUIS, and they are not expected to be effective as a reversal agent.

5.6 Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome

(Newly added subsection)

Direct-acting oral anticoagulants (DOACs), including ELIQUIS, are 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

In ARISTOTLE, the results for major bleeding were generally consistent across most major subgroups including age, weight, CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk), prior warfarin use, geographic region, and aspirin use at randomization (Figure 1). Subjects treated with ELIQUIS with diabetes bled more (3% per year) than did subjects without diabetes (1.9% per year).

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Less common adverse reactions in ELIQUIS-treated patients undergoing hip or knee replacement surgery occurring at a frequency of greater than or equal to 0.1% to <1%:

Blood and lymphatic system disorders: thrombocytopenia (including platelet count decreases)

Vascular disorders: hypotension (including procedural hypotension)

Respiratory, thoracic, and mediastinal disorders: epistaxis

Gastrointestinal disorders: gastrointestinal hemorrhage (including hematemesis and melena), hematochezia

Hepatobiliary disorders: liver function test abnormal, blood alkaline phosphatase increased, blood bilirubin increased

Renal and urinary disorders: hematuria (including respective laboratory parameters)

Injury, poisoning, and procedural complications: wound secretion, incision-site hemorrhage (including incision-site hematoma), operative hemorrhage

Less common adverse reactions in ELIQUIS-treated patients undergoing hip or knee replacement surgery occurring at a frequency of <0.1%:

…

7 Drug Interactions

7.3 Anticoagulants and Antiplatelet Agents

(Additions and/or revisions underlined)

Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding.

APPRAISE-2, a placebo-controlled clinical trial of ELIQUIS in high-risk, post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with ELIQUIS compared to placebo. The rate of ISTH major bleeding was 2.8% per year with ELIQUIS versus 0.6% per year with placebo in patients receiving single antiplatelet therapy and was 5.9% per year with ELIQUIS versus 2.5% per year with placebo in those receiving dual antiplatelet therapy.

In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on ELIQUIS from 1.8% per year to 3.4% per year and concomitant use of aspirin and warfarin increased the bleeding risk from 2.7% per year to 4.6% per year. In this clinical trial, there was limited (2.3%) use of dual antiplatelet therapy with ELIQUIS.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

The limited available data on ELIQUIS 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 4, 1 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.

Clinical Considerations

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 ELIQUIS, 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. ELIQUIS 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.

Data

Animal Data

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 21 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

Call your doctor or get medical help right away if you have any of these signs or symptoms of bleeding when taking ELIQUIS:

• unexpected bleeding, or bleeding that lasts a long time, such as:

  • unusual bleeding from the gums

  • nosebleeds that happen often

  • menstrual bleeding or vaginal bleeding that is heavier than normal

• bleeding that is severe or you cannot control

• red, pink, or brown urine

• red or black stools (looks like tar)

• cough up blood or blood clots

• vomit blood or your vomit looks like coffee grounds

• unexpected pain, swelling, or joint pain

• headaches, feeling dizzy or weak

• ELIQUIS is not for patients with artificial heart valves.

• Spinal or epidural blood clots (hematoma). People who take a blood thinner medicine (anticoagulant) like ELIQUIS, and have medicine injected into their spinal and epidural area, or have a spinal puncture have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if:

• a thin tube called an epidural catheter is placed in your back to give you certain medicine

• you take NSAIDs or a medicine to prevent blood from clotting

• you have a history of difficult or repeated epidural or spinal punctures

• you have a history of problems with your spine or have had surgery on your spine

If you take ELIQUIS and receive spinal anesthesia or have a spinal puncture, your doctor should watch you closely for symptoms of spinal or epidural blood clots or bleeding. Tell your doctor right away if you have tingling, numbness, or muscle weakness, especially in your legs and feet.

• ELIQUIS is not for use in people with antiphospholipid syndrome (APS), especially with positive triple antibody testing, who have a history of blood clots.

…

What should I tell my doctor before taking ELIQUIS? Before you take ELIQUIS, tell your doctor if you:

• have kidney or liver problems

• have antiphospholipid syndrome

• have any other medical condition

• have ever had bleeding problems

• are pregnant or plan to become pregnant. It is not known if ELIQUIS will harm your unborn baby.

• are breastfeeding or plan to breastfeed. It is not known if ELIQUIS passes into your breast milk. You and your doctor should decide if you will take ELIQUIS or breastfeed. You should not do both.

Tell all of your doctors and dentists that you are taking ELIQUIS. They should talk to the doctor who prescribed ELIQUIS for you, before you have any surgery, medical or dental procedure.

…

06/03/2019 (SUPPL-21)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

PLLR conversion; please refer to label for complete information.

06/28/2018 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Bleeding

(additions underlined)

…

Reversal of Anticoagulant Effect

An agent to reverse the anti-factor Xa activity of apixaban is available. The pharmacodynamic effect of ELIQUIS can be expected to persist for at least 24 hours after the last dose, i.e., for about two drug half-lives. Prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa may be considered, but have not been evaluated in clinical studies.  When PCCs are used, monitoring for the anticoagulation effect of apixaban using a clotting test (PT, INR, or aPTT) or anti-factor Xa (FXa) activity is not useful and is not recommended. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration.

…

02/09/2018 (SUPPL-18)

Approved Drug Label (PDF)

7 Drug Interactions

Additions and/or revisions underlined:

7.1 Combined P-gp and Strong CYP3A4 Inhibitors

For patients receiving ELIQUIS 5 mg or 10 mg twice daily, the dose of ELIQUIS should be decreased by 50% when coadministered with drugs that are combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir).

For patients receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with combined P-gp and strong CYP3A4 inhibitors.

Clarithromycin

Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic data suggest that no dose adjustment is necessary with concomitant administration with ELIQUIS.

7.2 Combined P-gp and Strong CYP3A4 Inducers

Avoid concomitant use of ELIQUIS with combined P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban.

8 Use in Specific Populations

8.5 Geriatric Use

Throughout this entire subsection, years of age is added following every numerical age.

07/20/2016 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

Bleeding

Reversal of Anticoagulant Effect

• A specific antidote for ELIQUIS is not available, and there is no established way to reverse bleeding in patients taking ELIQUIS. The pharmacodynamic effect of ELIQUIS can be expected to persist for at least 24 hours after the last dose, i.e., for about two drug half-lives. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical studies. When PCCs are used, monitoring for the anticoagulation effect of apixaban using a clotting test (PT, INR, or aPTT) or anti-factor Xa (FXa) activity is not useful and is not recommended. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration.

8 Use in Specific Populations

Renal Impairment (revised)

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

• The recommended dose is 2.5 mg twice daily in patients with at least two of the following characteristics:
  • age =80 years
  • body weight =60 kg
  • serum creatinine =1.5 mg/dL

Patients with End-Stage Renal Disease on Dialysis

• Clinical efficacy and safety studies with ELIQUIS did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of ELIQUIS at the usually recommended dose will result in concentrations of apixaban and pharmacodynamic activity similar to those observed in the ARISTOTLE study. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ARISTOTLE.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery, andTreatment of DVT and PE and Reduction in the Risk of Recurrence of DVT and PE

• No dose adjustment is recommended for patients with renal impairment, including those with ESRD on dialysis. Clinical efficacy and safety studies with ELIQUIS did not enroll patients with ESRD on dialysis or patients with a CrCl <15 mL/min; therefore, dosing ecommendations are based on pharmacokinetic and pharmacodynamic (anti-FXa activity) data in subjects with ESRD maintained on dialysis.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MG - How should I take ELIQUIS?

Addition of the following:

• If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take ELIQUIS.

 

PCI

Advise patients of the following: (addition of the following)

• How to take ELIQUIS if they cannot swallow, or require a nasogastric tube.
• What to do if a dose is missed.