The following serious 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 NVAF [see WARNINGS AND PRECAUTIONS]
- Spinal/epidural anesthesia or puncture [see WARNINGS AND PRECAUTIONS]
The most serious adverse reactions reported with SAVAYSA were related to bleeding [see WARNINGS AND PRECAUTIONS].
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 and Hokusai VTE studies including 11,130 patients exposed to SAVAYSA 60 mg and 7002 patients exposed to SAVAYSA 30 mg once daily [see Clinical Studies ].
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/min*
|Eventa||SAVAYSA 60 mgb N = 5417
N = 5485 n (%/year)
|SAVAYSA 60 mg vs. Warfarin HR (95% CI)|
|Major Bleedingc||357 (3.1)||431 (3.7)||0.84 (0.73, 0.97)|
|Intracranial Hemorrhage (ICH)d||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)|
|Gastrointestinal||205 (1.8)||150 (1.3)||1.40 (1.13, 1.73)|
|Fatal Bleeding||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)||—|
|CRNM Bleedinge||982 (9.4)||1132 (10.9)||0.87 (0.80, 0.95)|
|Abbreviations: HR = Hazard Ratio versus Warfarin, CI = Confidence Interval, n = number of patients with events, N = number of patients in Safety population, CRNM = Clinically Relevant Non-Major.
* During or within 2 days of stopping study treatment
a A subject can be included in multiple sub-categories if he/she had an event for those categories.
b 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
c 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).
d ICH includes primary hemorrhagic stroke, subarachnoid hemorrhage, epidural/subdural hemorrhage, and ischemic stroke with major hemorrhagic conversion.
e A Clinically Relevant Non-Major bleeding event was defined as an overt bleeding event that required medical attention, including those that may have resulted in diagnostic or therapeutic measures.
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
N= 5417 n (%/year)
N= 5485 n (%/year)
|Major Gastrointestinal (GI) Bleedinga||205 (1.78)||150 (1.27)|
|- Upper GI||123 (1.06)||88 (0.74)|
|- Lower GIb||85 (0.73)||64 (0.54)|
|GUSTOc Severe GI bleeding||16 (0.14)||17 (0.14)|
|Fatal GI bleeding||1 ( < 0.1)||2 ( < 0.1)|
|* During or within 2 days of stopping study treatment
aGI bleeding was defined by location as upper or lower GI
b Lower GI bleeding included anorectal bleeding
c GUSTO – Severe or life-threatening bleeding that caused hemodynamic compromise and requires intervention
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* Study
*During or within 2 days of stopping study treatment
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.
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
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 primary safety endpoint 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
|Clinically Relevant Bleedinga (Major /CRNM), n (%)||349 (8.5)||423 (10.3)|
|Major Bleedingb, 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 ≥ 2g/dL||40 (1.0)||33 (0.8)|
|Transfusion of ≥ 2 units of RBC||28 (0.7)||22 (0.5)|
|CRNM Bleedingc||298 (7.2)||368 (8.9)|
|Any Bleed||895 (21.7)||1056 (25.6)|
|Abbreviations: N=number of patients in the modified intent-to-treat population; n = number of events; CRNM = clinically relevant non-major
a Primary Safety Endpoint: Clinically Relevant Bleeding (composite of Major and CRNM).
b 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.
c 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.
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 (%)
(N=4122) n (%)
|Bleeding ADRs a|
|Vaginal b||158 (9.0)||126 (7.1)|
|Cutaneous soft tissue||245 (5.9)||414 (10.0)|
|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)|
|Rash||147 (3.6)||151 (3.7)|
|Abnormal liver function tests||322 (7.8)||322 (7.8)|
|Anemia||72 (1.7)||55 (1.3)|
|a Adjudicated Any Bleeding by location for all bleeding event categories (including Major and CRNM)
b Gender specific vaginal bleeding percentage is based on number of female subjects in each treatment group