Dosage & Administration
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Eliquis Prescribing Information
(A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.5), Warnings and Precautions (5.1), and Clinical Studies (14.1)].
(B) SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas may occur in patients treated with ELIQUIS 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:
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- use of indwelling epidural catheters
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- concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
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- a history of traumatic or repeated epidural or spinal punctures
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- a history of spinal deformity or spinal surgery
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- optimal timing between the administration of ELIQUIS and neuraxial procedures is not known
[see Warnings and Precautions (5.3)]
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions (5.3)].
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated [see Warnings and Precautions (5.3)].
Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
ELIQUIS is indicated to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in adult patients who have undergone hip or knee replacement surgery.
Treatment of Deep Vein Thrombosis
ELIQUIS is indicated for the treatment of adults with deep vein thrombosis (DVT).
Treatment of Pulmonary Embolism
ELIQUIS is indicated for the treatment of adults with pulmonary embolism (PE).
Reduction in the Risk of Recurrence of Deep Vein Thrombosis and Pulmonary Embolism
ELIQUIS is indicated to reduce the risk of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) in adult patients following initial therapy.
1.6 Treatment of Venous Thromboembolism and Reduction in the Risk of Recurrent Venous Thromboembolism in Pediatric Patients
ELIQUIS is indicated for the treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth and older after at least 5 days of initial anticoagulant treatment.
Combined P-gp and Strong CYP3A4 Inhibitors
For adult patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose by 50% when ELIQUIS is coadministered with drugs that are combined P-glycoprotein (P-gp) and strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, itraconazole, ritonavir) [see Clinical Pharmacology (12.3)].
In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with combined P-gp and strong CYP3A4 inhibitors [see Drug Interactions (7.1)].
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- 0.5 mg, pink, round, film-coated tablets for oral suspension packaged in packets.
1-count (0.5 mg), 3-count (1.5 mg), and 4-count (2 mg). - •
- 2.5 mg, yellow, round, biconvex, film-coated tablets with “893” debossed on one side and “2½” on the other side.
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- 5 mg, pink, oval-shaped, biconvex, film-coated tablets with “894” debossed on one side and “5” on the other side.
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- 0.15 mg, white to pale yellow powder for oral suspension, in a yellow opaque capsule marked “898”.
Pregnancy
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 [see Warnings and Precautions (5.3)].
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.
Lactation
Risk Summary
There are no data on the presence of apixaban or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Apixaban and/or its metabolites were present in the milk of rats (see Data). Because human exposure through milk is unknown, breastfeeding is not recommended during treatment with ELIQUIS.
Data
Animal Data
Maximal plasma concentrations were observed after 30 minutes following a single oral administration of a 5 mg dose to lactating rats. Maximal milk concentrations were observed 6 hours after dosing. The milk to plasma AUC (0-24) ratio is 30:1 indicating that apixaban can accumulate in milk. The concentrations of apixaban in animal milk does not necessarily predict the concentration of drug in human milk.
Females and Males of Reproductive Potential
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.
Pediatric Use
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)].
Geriatric Use
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.
Renal Impairment
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 [see Dosage and Administration (2.1)]:
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- age greater than or equal to 80 years
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- body weight less than or equal to 60 kg
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- serum creatinine greater than or equal to 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 [see Dosage and Administration (2.1)] will result in concentrations of apixaban and pharmacodynamic activity similar to those observed in the ARISTOTLE study [see Clinical Pharmacology (12.3)]. 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, and Treatment 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 [see Dosage and Administration (2.1)]. 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 recommendations are based on pharmacokinetic and pharmacodynamic (anti-FXa activity) data in subjects with ESRD maintained on dialysis [see Clinical Pharmacology (12.3)].
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).
| Postnatal age (gender) | Threshold eGFR used to define inadequate renal function (mL/min/1.73 m2) |
|---|---|
| Inadequate renal function was defined as <30% of 1 standard deviation (SD) below normal GFR for age and size as | |
| determined by the updated Schwartz formula for ages up to 2 years. Beyond 2 years of age, the qualifying GFR for | |
| the pediatric VTE study was ≥30 mL/min/1.73m2. | |
1 week (males and females) | <8 |
2–8 weeks (males and females) | <12 |
>8 weeks to <2 years (males and females) | <22 |
Hepatic Impairment
No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh class A).
Because patients with moderate hepatic impairment (Child-Pugh class B) may have intrinsic coagulation abnormalities and there is limited clinical experience with ELIQUIS in these patients, dosing recommendations cannot be provided [see Clinical Pharmacology (12.2)].
ELIQUIS is not recommended in patients with severe hepatic impairment (Child-Pugh class C) [see Clinical Pharmacology (12.2)].
ELIQUIS has not been studied in pediatric patients with hepatic impairment.
ELIQUIS is contraindicated in patients with the following conditions:
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- Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]
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- Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) [see Adverse Reactions (6.1)]