apixaban (apixaban 2.5 mg) Dailymed

•  Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation:
  •  The recommended dose is 5 mg orally twice daily. (2.1) 
  •  In patients with at least 2 of the following characteristics: age greater than or equal to 80 years, body weight less than or equal to 60 kg, or serum creatinine greater than or equal to 1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily. (2.1)
• Prophylaxis of DVT following hip or knee replacement surgery: 
  •   The recommended dose is 2.5 mg orally twice daily. (2.1) 

• Treatment of DVT and PE:  
  •   The recommended dose is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily. (2.1)

• Reduction in the risk of recurrent DVT and PE following initial therapy: 
  • The recommended dose is 2.5 mg taken orally twice daily. (2.1)

 

2.1 Recommended Dose

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

The recommended dose of apixaban tablets for most patients is 5 mg taken orally twice daily.

The recommended dose of apixaban tablets is 2.5 mg twice daily in patients with at least two of the following characteristics:

• age greater than or equal to 80 years • body weight less than or equal to 60 kg • serum creatinine greater than or equal to 1.5 mg/dL

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

The recommended dose of apixaban tablets 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 35 days. • In patients undergoing knee replacement surgery, the recommended duration of treatment is 12 days.

Treatment of DVT and PE

The recommended dose of apixaban tablets is 10 mg taken orally twice daily for the first 7 days of therapy. After 7 days, the recommended dose is 5 mg taken orally twice daily.

Reduction in the Risk of Recurrence of DVT and PE

The recommended dose of apixaban tablets is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE [see Clinical Studies (14.3)].

2.2 Missed Dose

If a dose of apixaban tablets is 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. The dose should not be doubled to make up for a missed dose.

2.3 Temporary Interruption for Surgery and Other Interventions

Apixaban tablets 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 [see Warnings and Precautions (5.2)] . Apixaban tablets 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. Bridging anticoagulation during the 24 to 48 hours after stopping apixaban tablets and prior to the intervention is not generally required. Apixaban tablets should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established.

2.4 Converting from or to apixaban

Switching from warfarin to apixaban: Warfarin should be discontinued and apixaban started when the international normalized ratio (INR) is below 2.0.

Switching from apixaban to warfarin:  apixaban affects INR, so that initial INR measurements during the transition to warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue apixaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of apixaban would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.

Switching from apixaban to anticoagulants other than warfarin (oral or parenteral): Discontinue apixaban and begin taking the new anticoagulant other than warfarin at the usual time of the next dose of apixaban.

Switching from anticoagulants other than warfarin (oral or parenteral) to apixaban: Discontinue the anticoagulant other than warfarin and begin taking apixaban at the usual time of the next dose of the anticoagulant other than warfarin.

2.5 Combined P-gp and Strong CYP3A4 Inhibitors

For patients receiving apixaban tablets doses of 5 mg or 10 mg twice daily, reduce the dose by 50% when  apixaban tablet 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 apixaban tablets with combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitors [see Drug Interactions (7.1)].

2.6 Administration Options

For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg 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 [see Clinical Pharmacology (12.3)]. Alternatively, apixaban tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube [see Clinical Pharmacology (12.3)]. Crushed apixaban tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours.

3 Dosage Forms & Strengths

• 2.5mg, yellow, round, film coated biconvex tablets debossed with "C31" on one side and plain on the other side.
• 5 mg, pink, oval, film coated biconvex tablets debossed with "C32"on one side and plain on the other side.

• Tablets: 2.5 mg and 5 mg (3)

4 Contraindications

Apixaban tablets are contraindicated in patients with the following conditions:

• Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse  Reactions(6.1)] • Severe  hypersensitivity  reaction  to  apixaban (e.g.,  anaphylactic  reactions)  [see  Adverse Reactions (6.1)]

• Active pathological bleeding (4)
• Severe hypersensitivity to apixaban (4)

5 Warnings And Precautions

• Apixaban can cause serious, potentially fatal, bleeding. Promptly evaluate signs and symptoms of blood loss. An agent to reverse the anti-factor Xa activity of apixaban is available (5.2)
• Prosthetic heart valves:  Apixaban use not recommended. (5.4)
• Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholid Syndrome: Apixaban Tablets are use not recommended. (5.6)

5.1 Increased Risk of Thrombotic Events after Premature Discontinuation

Premature discontinuation of any oral anticoagulant, including apixaban tablets, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from apixaban tablets to warfarin in clinical trials in atrial fibrillation patients. If apixaban tablets are discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.4) and Clinical Studies (14.1)].

5.2 Bleeding

Apixaban tablets increases the risk of bleeding and can cause serious, potentially fatal, bleeding [see Dosage and Administration (2.1) and Adverse Reactions (6.1)].

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) [see Drug Interactions (7.3)].

Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue apixaban tablets 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 apixaban tablets 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)].

Hemodialysis does not appear to have a substantial impact on apixaban exposure [see Clinical Pharmacology (12.3)]. 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 and aprotinin) in individuals receiving apixaban and they are not expected to be effective as a reversal agent.

5.3 Spinal/Epidural Anesthesia or Puncture

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.

The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of apixaban tablets. The next dose of apixaban tablets should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of apixaban tablets for 48 hours.

Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs or bowel, or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.

5.4 Patients with Prosthetic Heart Valves

The safety and efficacy of apixaban tablets have not been studied in patients with prosthetic heart valves. Therefore, use of apixaban tablets is not recommended in these patients.

5.5 Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy

Initiation of apixaban tablets are not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

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

Direct-acting oral anticoagulants (DOACs), including Apixaban Tablets, 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, anticardioplipin, 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

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  [see  Warnings  and Precautions (5.1)]

• Bleeding [see Warnings and Precautions (5.2)]

• Spinal/epidural anesthesia or puncture [see Warnings and Precautions (5.3)]


Most common adverse reactions (>1%) are related to bleeding. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Indoco Remedies Limited at +1-855-642-2594 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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  apixaban tablets was  evaluated  in  the  ARISTOTLE  and  AVERROES  studies  [see Clinical Studies (14)], including 11,284 patients exposed to apixaban tablets 5 mg twice daily and 602 patients exposed to apixaban tablets 2.5 mg twice daily. The duration of apixaban tablets 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 apixaban tablets and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on apixaban tablets 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*

	Apixaban 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 apixaban 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

	Apixaban 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 apixaban tablets.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

The safety of apixaban tablets has been evaluated in 1 Phase II and 3 Phase III studies including 5924 patients exposed to apixaban tablets 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 tablets 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
	Apixaban 2.5 mg po bid 35±3 days	Enoxaparin 40 mg sc qd 35±3 days	Apixaban 2.5 mg po bid 12±2 days	Enoxaparin 40 mg sc qd 12±2 days	Apixaban 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 apixaban (administered 12 to 24 hours post surgery). ‡   Includes 5 subjects with major bleeding events that occurred before the first dose of apixaban (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 uled in Table 4.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 uled in Table 4. Table 4: Adverse Reactions Occurring in ≥1% of Patients in Either Group Undergoing Hip or Knee Replacement Surgery

	Apixaban, 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 apixaban-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 apixaban-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 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.

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

AMPLIFY Study

The mean duration of exposure to apixaban was 154 days and to enoxaparin/warfarin was 152 days in the AMPLIFY study. Adverse reactions related to bleeding occurred in 417 (15.6%) apixaban-treated patients compared to 661 (24.6%) 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  study, apixaban 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

	Apixaban N=2676 n (%)	Enoxaparin/Warfarin 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 uled in Table 6.

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

	Apixaban 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 apixaban 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%)  apixaban-treated patients compared to 72 (8.7%) 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.

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

Table 7: Bleeding Results in the AMPLIFY-EXT Study

	Apixaban 2.5 mg bid N=840 n (%)	Apixaban 5 mg bid N=811 n (%)	Placebo N=826 n (%)
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  uled  in Table 8. Table 8: Adverse Reactions Occurring in ≥1% of Patients Undergoing Extended Treatment for DVT and PE in the AMPLIFY-EXT Study

	Apixaban 2.5 mg bid N=840 n (%)	Apixaban 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 apixaban-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