Savaysa

SAVAYSA is contraindicated in patients with:

• Active pathological bleeding
  [see

  5.3 Risk of Bleeding

  SAVAYSA increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss.

  Discontinue SAVAYSA in patients with active pathological bleeding.

  Concomitant use of drugs affecting hemostasis may increase the risk of bleeding. These include aspirin and other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)

  [see Drug Interactions (7.1)]

  .

  Reversal of Anticoagulant Effect

  There is no established way to reverse the anticoagulant effects of SAVAYSA, which can be expected to persist for approximately 24 hours after the last dose. The anticoagulant effect of SAVAYSA cannot be reliably monitored with standard laboratory testing. A specific reversal agent for edoxaban is not available. Hemodialysis does not significantly contribute to edoxaban clearance

  [see Clinical Pharmacology (12.3)]

  . Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of SAVAYSA. The use of prothrombin complex concentrates (PCC), or other procoagulant reversal agents such as activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) may be considered but has not been evaluated in clinical outcome studies

  [see Clinical Pharmacology (12.2)]

  . When PCCs are used, monitoring for anticoagulation effect of edoxaban using clotting test (PT, INR, or aPTT) or anti-FXa activity is not useful and is not recommended.

  and

  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.

  The safety of SAVAYSA was evaluated in the ENGAGE AF-TIMI 48, Hokusai VTE, and Hokusai VTE Cancer studies including 11,530 patients exposed to SAVAYSA 60 mg and 7124 patients exposed to SAVAYSA 30 mg once daily

  [see Clinical Studies (14)]

  .

  The ENGAGE AF-TIMI 48 Study

  In the ENGAGE AF-TIMI 48 study, the median study drug exposure for the SAVAYSA and warfarin treatment groups was 2.5 years.

  Bleeding was the most common reason for treatment discontinuation. Bleeding led to treatment discontinuation in 3.9% and 4.1% of patients in the SAVAYSA 60 mg and warfarin treatment groups, respectively.

  In the overall population, major bleeding was lower in the SAVAYSA group compared to the warfarin group [HR 0.80 (0.70, 0.91), p < 0.001]. Table 6.1 shows major bleeding events (percentage of patients with at least one bleeding event, per year) for the indicated population (CrCL ≤ 95 mL/min).

  Table 6.1: Adjudicated Bleeding Events for NVAF Patients with CrCL ≤ 95 mL/minThe on-treatment period is during treatment or within 2 days of stopping study treatment. The difference in hemorrhagic stroke rate from Table 14.1 is because Table 14.1 includes events occurring during treatment or within 3 days of stopping study treatment and this table only includes patients with CrCL ≤ 95 mL/min.

  EventA subject can be included in multiple sub-categories if he/she had an event for those categories.	SAVAYSA 60 mgIncludes all patients with CrCL ≤ 95 mL/min randomized to receive 60 mg once daily, including those who were dose-reduced to 30 mg once daily because of prespecified baseline conditions. N = 5417 n (%/year)	Warfarin N = 5485 n (%/year)	SAVAYSA 60 mg vs. Warfarin HR (95% CI)
  Abbreviations: HR = Hazard Ratio versus Warfarin, CI = Confidence Interval, n = number of patients with events, N = number of patients in Safety population,
  Major BleedingA major bleeding event (the study primary safety endpoint) was defined as clinically overt bleeding that met one of the following criteria: fatal bleeding; symptomatic bleeding in a critical site such as retroperitoneal, intracranial, intraocular, intraspinal, intra-articular, pericardial, or intramuscular with compartment syndrome; a clinically overt bleeding event that caused a fall in hemoglobin of at least 2.0 g/dL (or a fall in hematocrit of at least 6.0% in the absence of hemoglobin data), when adjusted for transfusions (1 unit of transfusion = 1.0 g/dL drop in hemoglobin).	357 (3.1)	431 (3.7)	0.84 (0.73, 0.97)
  Intracranial Hemorrhage (ICH)ICH includes primary hemorrhagic stroke, subarachnoid hemorrhage, epidural/subdural hemorrhage, and ischemic stroke with major hemorrhagic conversion.	53 (0.5)	122 (1.0)	0.44 (0.32, 0.61)
  Hemorrhagic Stroke	33 (0.3)	69 (0.6)	0.49 (0.32, 0.74)
  Other ICH	20 (0.2)	55 (0.5)	0.37 (0.22, 0.62)
  GastrointestinalGastrointestinal (GI) bleeds include bleeding from upper and lower GI tract. Lower GI tract bleeding includes rectal bleeds.	205 (1.8)	150 (1.3)	1.40 (1.13, 1.73)
  Fatal BleedingFatal bleed is a bleeding event during the on-treatment period and adjudicated as leading directly to death within 7 days.	21 (0.2)	42 (0.4)	0.51 (0.30, 0.86)
  ICH	19 (0.2)	36 (0.3)	0.54 (0.31, 0.94)
  Non-intracranial	2 (< 0.1)	6 (< 0.1)	----

  The most common site of a major bleeding event was the gastrointestinal (GI) tract. Table 6.2 shows the number of and the rate at which patients experienced GI bleeding in the SAVAYSA 60 mg and warfarin treatment groups.

  Table 6.2: Gastrointestinal Bleeding Events for NVAF Patients with CrCL ≤ 95 mL/minDuring or within 2 days of stopping study treatment

  	SAVAYSA N = 5417 n (%/year)	Warfarin N = 5485 n (%/year)
  Major Gastrointestinal (GI) BleedingGI bleeding was defined by location as upper or lower GI	205 (1.78)	150 (1.27)
  Upper GI	123 (1.06)	88 (0.74)
  Lower GILower GI bleeding included anorectal bleeding	85 (0.73)	64 (0.54)
  GUSTOGUSTO – Severe or life-threatening bleeding that caused hemodynamic compromise and requires interventionSevere GI bleeding	16 (0.14)	17 (0.14)
  Fatal GI bleeding	1 (< 0.1)	2 (< 0.1)

  The rate of anemia-related adverse events was greater with SAVAYSA 60 mg than with warfarin (9.6% vs. 6.8%).

  The comparative rates of major bleeding on SAVAYSA and warfarin were generally consistent among subgroups (

  see Figure 6.1

  ). Bleeding rates appeared higher in both treatment arms (SAVAYSA and warfarin) in the following subgroups of patients: those receiving aspirin, those in the United States, those more than 75 years old and those with reduced renal function.

  Figure 6.1: Adjudicated Major Bleeding in the ENGAGE AF-TIMI 48During or within 2 days of stopping study treatmentStudy
  Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. 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.

  Figure 6.1

  Other Adverse Reactions

  The most common non-bleeding adverse reactions (≥ 1%) for SAVAYSA 60 mg versus warfarin were rash (4.2% vs. 4.1%), and abnormal liver function tests (4.8% vs. 4.6%), respectively.

  Interstitial Lung Disease (ILD) was reported as a serious adverse event on treatment for SAVAYSA 60 mg and warfarin in 15 (0.2%) and 7 (0.1%) patients, respectively. Many of the cases in both treatment groups were confounded by the use of amiodarone, which has been associated with ILD, or by infectious pneumonia. In the overall study period, there were 5 and 0 fatal ILD cases in the SAVAYSA 60 mg and warfarin groups, respectively.

  The Hokusai VTE Study

  The safety of SAVAYSA in the treatment of VTE was assessed in the Hokusai VTE study. The duration of drug exposure for SAVAYSA was ≤ 6 months for 1561 (37.9%) of patients, > 6 months for 2557 (62.1%) of patients and 12 months for 1661 (40.3%) of patients.

  Bleeding was the most common reason for treatment discontinuation and occurred in 1.4% and 1.4% of patients in the SAVAYSA and warfarin arms, respectively.

  Bleeding in Patients with DVT and/or PE in the Hokusai VTE Study

  The major safety outcome was Clinically Relevant Bleeding, defined as the composite of Major and Clinically Relevant Non-Major (CRNM) Bleeding that occurred during or within three days of stopping study treatment. The incidence of Clinically Relevant Bleeding was lower in SAVAYSA than warfarin [HR (95% CI): 0.81 (0.71, 0.94); p = 0.004].

  Table 6.3 shows the number of patients experiencing bleeding events in the Hokusai VTE Study.

  Table 6.3: Bleeding Events in the Hokusai VTE Study

  	SAVAYSA (N = 4118)	Warfarin (N = 4122)
  Abbreviations: N = number of patients in the modified intent-to-treat population; n = number of events; CRNM = clinically relevant non-major
  Clinically Relevant BleedingPrimary Safety Endpoint: Clinically Relevant Bleeding (composite of Major and CRNM).(Major/CRNM), n (%)	349 (8.5)	423 (10.3)
  Major BleedingA major bleeding event was defined as clinically overt bleeding that met one of the following criteria: associated with a fall in hemoglobin level of 2.0 g/dL or more, or leading to transfusion of two or more units of packed red cells or whole blood; occurring in a critical site or organ: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; contributing to death., n (%)	56 (1.4)	66 (1.6)
  Fatal bleeding	2 (<0.1)	10 (0.2)
  Intracranial fatal	0 (0.0)	6 (0.1)
  Non-fatal critical organ bleeding	13 (0.3)	25 (0.6)
  Intracranial bleeding	5 (0.1)	12 (0.3)
  Non-fatal non-critical organ bleeding	41 (1.0)	33 (0.8)
  Decrease in Hb ≥ 2 g/dL	40 (1.0)	33 (0.8)
  Transfusion of ≥ 2 units of RBC	28 (0.7)	22 (0.5)
  CRNM BleedingCRNM bleeding was defined as overt bleeding not meeting the criteria for a major bleeding event but that was associated with a medical intervention, an unscheduled contact (visit or telephone call) with a physician, temporary cessation of study treatment, or associated with discomfort for the subject such as pain, or impairment of activities of daily life.	298 (7.2)	368 (8.9)
  Any Bleed	895 (21.7)	1056 (25.6)

  Patients with low body weight (≤ 60 kg), CrCL ≤ 50 mL/min, or concomitant use of select P-gp inhibitors were randomized to receive SAVAYSA 30 mg or warfarin. As compared to all patients who received SAVAYSA or warfarin in the 60 mg cohort, all patients who received SAVAYSA or warfarin in the 30 mg cohort (n = 1452, 17.6% of the entire study population) were older (60.1 vs 54.9 years), more frequently female (66.5% vs 37.7%), more frequently of Asian race (46.0% vs 15.6%) and had more co-morbidities (e.g., history of bleeding, hypertension, diabetes, cardiovascular disease, cancer). Clinically relevant bleeding events occurred in 58/733 (7.9%) of the SAVAYSA patients receiving 30 mg once daily and 92/719 (12.8%) of warfarin patients meeting the above criteria.

  In the Hokusai VTE study, among all patients the most common bleeding adverse reactions (≥ 1%) are shown in Table 6.4.

  Table 6.4: Adverse Reactions Occurring in ≥ 1% of Patients Treated in Hokusai VTE

  	SAVAYSA 60 mg (N = 4118) n (%)	Warfarin (N = 4122) n (%)
  Bleeding ADRs Adjudicated Any Bleeding by location for all bleeding event categories (including Major and CRNM)
  VaginalGender specific vaginal bleeding percentage is based on number of female subjects in each treatment group	158 (9)	126 (7.1)
  Cutaneous soft tissue	245 (5.9)	414 (10)
  Epistaxis	195 (4.7)	237 (5.7)
  Gastrointestinal bleeding	171 (4.2)	150 (3.6)
  Lower gastrointestinal	141 (3.4)	126 (3.1)
  Oral/pharyngeal	138 (3.4)	162 (3.9)
  Macroscopic hematuria/urethral	91 (2.2)	117 (2.8)
  Puncture site	56 (1.4)	99 (2.4)
  Non-Bleeding ADRs
  Rash	147 (3.6)	151 (3.7)
  Abnormal liver function tests	322 (7.8)	322 (7.8)
  Anemia	72 (1.7)	55 (1.3)

  Bleeding in Patients with VTE in the Hokusai VTE Cancer Study

  The safety of SAVAYSA in patients with cancer and VTE was evaluated in the Hokusai VTE Cancer study

  [see Clinical Studies (14.2)]

  . The median duration of SAVAYSA exposure was 211 days (range, 2 to 423). The safety outcome was major bleeding that occurred during or within three days of stopping study treatment. The incidence of major bleeding was higher in the SAVAYSA arm than in the dalteparin arm [HR (95% CI): 2.00 (1.09, 3.66)].

  Table 6.5 presents the bleeding results from the Hokusai VTE Cancer study.

  Table 6.5: Bleeding Events in the Hokusai VTE Cancer Study

  	SAVAYSA (N = 522)	Dalteparin (N = 524)
  Abbreviations: N = number of patients in the modified intent-to-treat population; n = number of events; CRNM = clinically relevant non-major
  Major BleedingA major bleeding event was defined as clinically overt bleeding that met one of the following criteria: associated with a fall in hemoglobin level of 2.0 g/dL or more, or leading to transfusion of two or more units of packed red cells or whole blood; occurring in a critical site or organ: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; contributing to death., n (%)	32 (6.1%)	16 (3.1%)
  Fatal bleeding	1 (0.2%)All events in this table, except for the fatal bleeding event on SAVAYSA, are based on adjudicated events. The fatal bleeding event on SAVAYSA was adjudicated as a major bleed; however, the adjudicated cause of death was cancer-related death.	2 (0.4%)
  Intracranial	0	1 (0.2%)
  Lower gastrointestinal	1 (0.2%)	1 (0.2%)
  Non-fatal critical organ bleeding	5 (1%)	6 (1.1%)
  Intracranial bleeding	2 (0.4%)	2 (0.4%)
  Non-fatal non-critical organ bleeding	27 (5.2%)	8 (1.5%)
  Gastrointestinal	22 (4.2%)	4 (0.8%)
  Upper gastrointestinal	18 (3.4%)	3 (0.6%)
  Lower gastrointestinal	3 (0.6%)	1 (0.2%)
  Decrease in Hb ≥ 2 g/dL	28 (5.4%)	11 (2.1%)
  CRNM BleedingCRNM bleeding was defined as overt bleeding not meeting the criteria for a major bleeding event but that was associated with a medical intervention, an unscheduled contact (visit or telephone call) with a physician, temporary cessation of study treatment, or associated with discomfort for the subject such as pain or impairment of activities of daily life., n (%)	70 (13.4%)	48 (9.2%)
  Any Bleeding, n (%)	137 (26.2%)	104 (19.8%)

  In patients with GI cancer at randomization, major bleeding occurred in 13.2% (18/136) in the SAVAYSA group and 2.4% (3/125) in the dalteparin group. In patients without GI cancer at randomization, major bleeding occurred in 3.6% (14/386) in the SAVAYSA group and 3.3% (13/399) in the dalteparin group.

  ]
  .