Edoxabanside effects

The following clinically significant adverse reactions are discussed in greater detail in other sections of the prescribing information. Increased Risk of Stroke with Discontinuation of SAVAYSA in Patients with Nonvalvular Atrial Fibrillation Risk of Bleeding Spinal/Epidural Anesthesia or Puncture Treatment of NVAF: The most common adverse reactions (≥ 5%) are bleeding and anemia Treatment of DVT and PE: The most common adverse reactions (≥ 1%) are bleeding, rash, abnormal liver function tests and anemia To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 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. 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. 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, 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/min The 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. Event A subject can be included in multiple sub-categories if he/she had an event for those categories. SAVAYSA 60 mg Includes 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 Bleeding A 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). 357 431

0.84 Intracranial

Hemorrhage (ICH) ICH includes primary hemorrhagic stroke, subarachnoid hemorrhage, epidural/subdural hemorrhage, and ischemic stroke with major hemorrhagic conversion. 53 122

0.44 Hemorrhagic

Stroke 33 69 0.49 Other ICH 20 55

0.37 Gastrointestinal

Gastrointestinal (GI) bleeds include bleeding from upper and lower GI tract. Lower GI tract bleeding includes rectal bleeds. 205 150

1.40 Fatal Bleeding

Fatal bleed is a bleeding event during the on-treatment period and adjudicated as leading directly to death within 7 days. 21 42 0.51 ICH 19 36 0.54 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/min During or within 2 days of stopping study treatment SAVAYSA N = 5417 n (%/year) Warfarin N = 5485 n (%/year) Major Gastrointestinal (GI) Bleeding GI bleeding was defined by location as upper or lower GI 205 150 Upper GI 123 88 Lower GI Lower GI bleeding included anorectal bleeding 85 64 GUSTO GUSTO – Severe or life-threatening bleeding that caused hemodynamic compromise and requires intervention Severe GI bleeding 16 17 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 48 During or within 2 days of stopping study treatment Study 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; 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 Bleeding Primary Safety Endpoint: Clinically Relevant Bleeding (composite of Major and CRNM). (Major/CRNM), n (%) 349 423 Major Bleeding A 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 66 Fatal bleeding 2 (<0.1) 10 Intracranial fatal 0 6 Non-fatal critical organ bleeding 13 25 Intracranial bleeding 5 12 Non-fatal non-critical organ bleeding 41 33 Decrease in Hb ≥ 2 g/dL 40 33 Transfusion of ≥ 2 units of RBC 28 22 CRNM Bleeding CRNM 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. 298 368 Any Bleed 895 1056 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) Vaginal Gender specific vaginal bleeding percentage is based on number of female subjects in each treatment group 158 126 Cutaneous soft tissue 245 414 Epistaxis 195 237 Gastrointestinal bleeding 171 150 Lower gastrointestinal 141 126 Oral/pharyngeal 138 162 Macroscopic hematuria/urethral 91 117 Puncture site 56 99 Non-Bleeding ADRs Rash 147 151 Abnormal liver function tests 322 322 Anemia 72 55 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. 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 ]. 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 Bleeding A 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 Bleeding CRNM 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.

6.2 Postmarketing

Experience The following adverse reactions have been identified during post-approval use of SAVAYSA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: thrombocytopenia Gastrointestinal disorders: abdominal pain Immune system disorders: angioedema, hypersensitivity Nervous system disorders: dizziness, headache Renal and urinary disorders: anticoagulant-related nephropathy Skin and subcutaneous tissue disorders: urticaria