SIDE EFFECTS

The following clinically significant adverse reactions are discussed in greater detail in other sections of the prescribing information.

• Increased Risk of Thrombotic Events After Premature Discontinuation
• Bleeding
• Spinal/Epidural Anesthesia or Puncture

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Reduction Of Risk Of Stroke And Systemic Embolism In Patients With Nonvalvular Atrial Fibrillation

The safety of ELIQUIS was evaluated in the ARISTOTLE and AVERROES studies, including 11,284 patients exposed to ELIQUIS 5 mg twice daily and 602 patients exposed to ELIQUIS 2.5 mg twice daily. The duration of ELIQUIS exposure was ≥12 months for 9375 patients and ≥24 months for 3369 patients in the two studies. In ARISTOTLE, the mean duration of exposure was 89 weeks (>15,000 patient-years). In AVERROES, the mean duration of exposure was approximately 59 weeks (>3000 patient-years).

The most common reason for treatment discontinuation in both studies was for bleeding-related adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients treated with ELIQUIS and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on ELIQUIS and aspirin, respectively.

Bleeding In Patients With Nonvalvular Atrial Fibrillation In ARISTOTLE And AVERROES

Tables 1 and 2 show the number of patients experiencing major bleeding during the treatment period and the bleeding rate (percentage of subjects with at least one bleeding event per 100 patient-years) in ARISTOTLE and AVERROES.

Table 1: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE*

	ELIQUIS N=9088 n (per 100 pt-year)	Warfarin N=9052 n (per 100 pt-year)	Hazard Ratio (95% CI)	P-value
Major†	327 (2.13)	462 (3.09)	0.69 (0.60, 0.80)	<0.0001
Intracranial (ICH)‡	52 (0.33)	125 (0.82)	0.41 (0.30, 0.57)	–
Hemorrhagic stroke§	38 (0.24)	74 (0.49)	0.51 (0.34, 0.75)	–
Other ICH	15 (0.10)	51 (0.34)	0.29 (0.16, 0.51)	–
Gastrointestinal (GI)¶	128 (0.83)	141 (0.93)	0.89 (0.70, 1.14)	–
Fatal**	10 (0.06)	37 (0.24)	0.27 (0.13, 0.53)	–
Intracranial	4 (0.03)	30 (0.20)	0.13 (0.05, 0.37)	–
Non-intracranial	6 (0.04)	7 (0.05)	0.84 (0.28, 2.15)	–
* Bleeding events within each subcategory were counted once per subject, but subjects may have contributed events to multiple endpoints. Bleeding events were counted during treatment or within 2 days of stopping study treatment (on-treatment period). † Defined as clinically overt bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥2 g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal or with fatal outcome. † Intracranial bleed includes intracerebral, intraventricular, subdural, and subarachnoid bleeding. Any type of hemorrhagic stroke was adjudicated and counted as an intracranial major bleed. § On-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14. ¶ GI bleed includes upper GI, lower GI, and rectal bleeding. **Fatal bleeding is an adjudicated death with the primary cause of death as intracranial bleeding or non-intracranial bleeding during the on-treatment period.

 

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).

Figure 1: Major Bleeding Hazard Ratios by Baseline Characteristics – ARISTOTLE Study

 

Note: The figure above presents effects in various subgroups, all of which are baseline characteristics and all of which were prespecified, if not the groupings. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Table 2: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in AVERROES

	ELIQUIS N=2798 n (%/year)	Aspirin N=2780 n (%/year)	Hazard Ratio (95% CI)	P-value
Major	45 (1.41)	29 (0.92)	1.54 (0.96, 2.45)	0.07
Fatal	5 (0.16)	5 (0.16)	0.99 (0.23, 4.29)	–
Intracranial	11 (0.34)	11 (0.35)	0.99 (0.39, 2.51)	–
Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.

 

Other Adverse Reactions

Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and anaphylactic reactions, such as allergic edema) and syncope were reported in <1% of patients receiving ELIQUIS.

Prophylaxis Of Deep Vein Thrombosis Following Hip Or Knee Replacement Surgery

The safety of ELIQUIS has been evaluated in 1 Phase II and 3 Phase III studies including 5924 patients exposed to ELIQUIS 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 ELIQUIS 2.5 mg twice daily experienced adverse reactions.

Bleeding results during the treatment period in the Phase III studies are shown in Table 3. Bleeding was assessed in each study beginning with the first dose of double-blind study drug.

Table 3: Bleeding During the Treatment Period in Patients Undergoing Elective Hip or Knee Replacement Surgery

Bleeding Endpoint*	ADVANCE-3 Hip Replacement Surgery		ADVANCE-2 Knee Replacement Surgery		ADVANCE-1 Knee Replacement Surgery
	ELIQUIS 2.5 mg po bid 35±3 days	Enoxaparin 40 mg sc qd 35±3 days	ELIQUIS 2.5 mg po bid 12±2 days	Enoxaparin 40 mg sc qd 12±2 days	ELIQUIS 2.5 mg po bid 12±2 days	Enoxaparin 30 mg sc q12h 12±2 days
	First dose 12 to 24 hours post surgery	First dose 9 to 15 hours prior to surgery	First dose 12 to 24 hours post surgery	First dose 9 to 15 hours prior to surgery	First dose 12 to 24 hours post surgery	First dose 12 to 24 hours post surgery
All treated	N=2673	N=2659	N=1501	N=1508	N=1596	N=1588
Major (including surgical site)	22 (0.82%)†	18 (0.68%)	9 (0.60%)‡	14 (0.93%)	11 (0.69%)	22 (1.39%)
Fatal	0	0	0	0	0	1 (0.06%)
Hgb decrease ≥2 g/dL	13 (0.49%)	10 (0.38%)	8 (0.53%)	9 (0.60%)	10 (0.63%)	16 (1.01%)
Transfusion of ≥2 units RBC	16 (0.60%)	14 (0.53%)	5 (0.33%)	9 (0.60%)	9 (0.56%)	18 (1.13%)
Bleed at critical site§	1 (0.04%)	1 (0.04%)	1 (0.07%)	2 (0.13%)	1 (0.06%)	4 (0.25%)
Major + CRNM¶	129 (4.83%)	134 (5.04%)	53 (3.53%)	72 (4.77%)	46 (2.88%)	68 (4.28%)
All	313 (11.71%)	334 (12.56%)	104 (6.93%)	126 (8.36%)	85 (5.33%)	108 (6.80%)
* All bleeding criteria included surgical site bleeding. † Includes 13 subjects with major bleeding events that occurred before the first dose of ELIQUIS (administered 12 to 24 hours post-surgery). † Includes 5 subjects with major bleeding events that occurred before the first dose of ELIQUIS (administered 12 to 24 hours post-surgery). § Intracranial, intraspinal, intraocular, pericardial, an operated joint requiring re-operation or intervention, intramuscular with compartment syndrome, or retroperitoneal. Bleeding into an operated joint requiring re-operation or intervention was present in all patients with this category of bleeding. Events and event rates include one enoxaparin-treated patient in ADVANCE-1 who also had intracranial hemorrhage. ¶ CRNM = clinically relevant nonmajor.

 

Adverse reactions occurring in ≥1% of patients undergoing hip or knee replacement surgery in the 1 Phase II study and the 3 Phase III studies are listed in Table 4.

Table 4: Adverse Reactions Occurring in ≥1% of Patients in Either Group Undergoing Hip or Knee Replacement Surgery

	ELIQUIS, n (%) 2.5 mg po bid N=5924	Enoxaparin, n (%) 40 mg sc qd or 30 mg sc q12h N=5904
Nausea	153 (2.6)	159 (2.7)
Anemia (including postoperative and hemorrhagic anemia, and respective laboratory parameters)	153 (2.6)	178 (3.0)
Contusion	83 (1.4)	115 (1.9)
Hemorrhage (including hematoma, and vaginal and urethral hemorrhage)	67 (1.1)	81 (1.4)
Postprocedural hemorrhage (including postprocedural hematoma, wound hemorrhage, vessel puncture-site hematoma, and catheter-site hemorrhage)	54 (0.9)	60 (1.0)
Transaminases increased (including alanine aminotransferase increased and alanine aminotransferase abnormal)	50 (0.8)	71 (1.2)
Aspartate aminotransferase increased	47 (0.8)	69 (1.2)
Gamma-glutamyltransferase increased	38 (0.6)	65 (1.1)

 

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

Gingival bleeding, hemoptysis, hypersensitivity, muscle hemorrhage, ocular hemorrhage (including conjunctival hemorrhage), rectal hemorrhage

Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT or PE

The safety of ELIQUIS has been evaluated in the AMPLIFY and AMPLIFY-EXT studies, including 2676 patients exposed to ELIQUIS 10 mg twice daily, 3359 patients exposed to ELIQUIS 5 mg twice daily, and 840 patients exposed to ELIQUIS 2.5 mg twice daily.

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

AMPLIFY Study

The mean duration of exposure to ELIQUIS was 154 days and to enoxaparin/warfarin was 152 days in the AMPLIFY study. Adverse reactions related to bleeding occurred in 417 (15.6%) ELIQUIS-treated patients compared to 661 (24.6%) enoxaparin/warfarin-treated patients. The discontinuation rate due to bleeding events was 0.7% in the ELIQUIS-treated patients compared to 1.7% in enoxaparin/warfarin-treated patients in the AMPLIFY study.

In the AMPLIFY study, ELIQUIS was statistically superior to enoxaparin/warfarin in the primary safety endpoint of major bleeding (relative risk 0.31, 95% CI [0.17, 0.55], P-value <0.0001).

Bleeding results from the AMPLIFY study are summarized in Table 5.

Table 5: Bleeding Results in the AMPLIFY Study

	ELIQUIS N=2676 n (%)	Enoxaparin/W arfarin N=2689 n (%)	Relative Risk (95% CI)
Major	15 (0.6)	49 (1.8)	0.31 (0.17, 0.55) p<0.0001
CRNM*	103 (3.9)	215 (8.0)
Major + CRNM	115 (4.3)	261 (9.7)
Minor	313 (11.7)	505 (18.8)
All	402 (15.0)	676 (25.1)
* CRNM = clinically relevant nonmajor bleeding. Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.

 

Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in Table 6.

Table 6: Adverse Reactions Occurring in ≥1% of Patients Treated for DVT and PE in the AMPLIFY Study

	ELIQUIS N=2676 n (%)	Enoxaparin/Warfarin N=2689 n (%)
Epistaxis	77 (2.9)	146 (5.4)
Contusion	49 (1.8)	97 (3.6)
Hematuria	46 (1.7)	102 (3.8)
Menorrhagia	38 (1.4)	30 (1.1)
Hematoma	35 (1.3)	76 (2.8)
Hemoptysis	32 (1.2)	31 (1.2)
Rectal hemorrhage	26 (1.0)	39 (1.5)
Gingival bleeding	26 (1.0)	50 (1.9)

 

AMPLIFY-EXT Study

The mean duration of exposure to ELIQUIS was approximately 330 days and to placebo was 312 days in the AMPLIFY-EXT study. Adverse reactions related to bleeding occurred in 219 (13.3%) ELIQUIS-treated patients compared to 72 (8.7%) placebo-treated patients. The discontinuation rate due to bleeding events was approximately 1% in the ELIQUIS-treated patients compared to 0.4% in those patients in the placebo group in the AMPLIFY-EXT study.

Bleeding results from the AMPLIFY-EXT study are summarized in Table 7.

Table 7: Bleeding Results in the AMPLIFY-EXT Study

	ELIQUIS 2.5 mg bid N=840n (%)	ELIQUIS 5 mg bid N=811n (%)	Placebo N=826n (%)
Major	2 (0.2)	1 (0.1)	4 (0.5)
CRNM*	25 (3.0)	34 (4.2)	19 (2.3)
Major + CRNM	27 (3.2)	35 (4.3)	22 (2.7)
Minor	75 (8.9)	98 (12.1)	58 (7.0)
All	94 (11.2)	121 (14.9)	74 (9.0)
* CRNM = clinically relevant nonmajor bleeding. Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.

 

Adverse reactions occurring in ≥1% of patients in the AMPLIFY-EXT study are listed in Table 8.

Table 8: Adverse Reactions Occurring in ≥1% of Patients Undergoing Extended Treatment for DVT and PE in the AMPLIFY-EXT Study

	ELIQUIS 2.5 mg bid N=840 n (%)	ELIQUIS 5 mg bid N=811 n (%)	Placebo N=826 n (%)
Epistaxis	13 (1.5)	29 (3.6)	9 (1.1)
Hematuria	12 (1.4)	17 (2.1)	9 (1.1)
Hematoma	13 (1.5)	16 (2.0)	10 (1.2)
Contusion	18 (2.1)	18 (2.2)	18 (2.2)
Gingival bleeding	12 (1.4)	9 (1.1)	3 (0.4)

 

Other Adverse Reactions

Less common adverse reactions in ELIQUIS-treated patients in the AMPLIFY or AMPLIFY-EXT studies occurring at a frequency of ≥0.1% to <1%:

Blood and lymphatic system disorders: hemorrhagic anemia

Gastrointestinal disorders: hematochezia, hemorrhoidal hemorrhage, gastrointestinal hemorrhage, hematemesis, melena, anal hemorrhage

Injury, poisoning, and procedural complications: wound hemorrhage, postprocedural hemorrhage, traumatic hematoma, periorbital hematoma

Musculoskeletal and connective tissue disorders: muscle hemorrhage

Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia, menometrorrhagia, genital hemorrhage

Vascular disorders: hemorrhage

Skin and subcutaneous tissue disorders: ecchymosis, skin hemorrhage, petechiae

Eye disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage

Investigations: blood urine present, occult blood positive, occult blood, red blood cells urine positive

General disorders and administration-site conditions: injection-site hematoma, vessel puncture-site hematoma.

 

SRC: NLM .