Savaysa
- Generic Name: edoxaban tablets
- Brand Name: Savaysa
- Drug Class: Factor Xa Inhibitors
Savaysa (Edoxaban Tablets) side effects drug center
Savaysa Side Effects Center
What Is Savaysa?
Savaysa (edoxaban) is a factor Xa inhibitor used to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).
What Are Side Effects of Savaysa?
Common side effects of Savaysa include:
- bleeding,
- easy bruising,
- nosebleeds,
- rash,
- abnormal liver function tests, and
- low red blood cell count (anemia).
Dosage for Savaysa
The recommended dose of Savaysa is 60 mg taken orally once daily.
What Drugs, Substances, or Supplements Interact with Savaysa?
Savaysa may interact with anticoagulants, antiplatelet drugs, thrombolytics, and rifampin. Tell your doctor all medications and supplements you use.
Savaysa During Pregnancy and Breastfeeding
During pregnancy, Savaysa should only be used if prescribed. This drug is not recommended for use while breastfeeding.
Additional Information
Our Savaysa (edoxaban) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
Savaysa Consumer Information
Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.
Also seek emergency medical attention if you have symptoms of a spinal blood clot: back pain, numbness or muscle weakness in your lower body, or loss of bladder or bowel control.
Edoxaban can cause you to bleed more easily. Call your doctor at once if you have signs of bleeding such as:
- easy bruising or bleeding (nosebleeds, bleeding gums, heavy menstrual bleeding);
- pain, swelling, or drainage from a wound or where a needle was injected in your skin;
- bleeding from wounds or needle injections, any bleeding that will not stop;
- headaches, dizziness, weakness, feeling like you might pass out;
- urine that looks red, pink, or brown; or
- bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds.
Common side effects may include:
- bleeding; or
- low red blood cells (anemia)--pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands and feet.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Read the entire detailed patient monograph for Savaysa (Edoxaban Tablets)
Savaysa Professional Information
SIDE 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 [see WARNINGS AND PRECAUTIONS]
- Risk of Bleeding [see WARNINGS AND PRECAUTIONS]
- Spinal/Epidural Anesthesia or Puncture [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, 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].
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 (%/year) |
Warfarin 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) |
| Gastrointestinale | 205 (1.8) | 150 (1.3) | 1.40 (1.13, 1.73) |
| Fatal Bleedingf | 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) | - |
| Abbreviations: HR = Hazard Ratio versus Warfarin, CI = Confidence Interval, n = number of patients with events, N = number of patients in Safety population, * 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. 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 Gastrointestinal (GI) bleeds include bleeding from upper and lower GI tract. Lower GI tract bleeding includes rectal bleeds. f Fatal bleed is a bleeding event during the on-treatment period and adjudicated as leading directly to death within 7 days. |
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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*
| SAVAYSA N = 5417 n (%/year) |
Warfarin 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) |
| GUSTO Severe GI bleeding | 16 (0.14) | 17 (0.14) |
| Fatal GI bleeding | 1 ( < 0.1) | 12 ( < 0.1) |
| * During or within 2 days of stopping study treatment a GI 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 |
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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
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) |
|
| 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 ≥ 2 g/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. |
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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 ADRsa | ||
| Vaginalb | 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) |
| 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 |
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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]. 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) |
|
| Major Bleeding*, n(%) | 32 (6.1%) | 16 (3.1%) |
| Fatal bleeding | 1 (0.2%)† | 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‡, n (%) | 70 (13.4%) | 48 (9.2%) |
| Any Bleeding, n (%) | 137 (26.2%) | 104 (19.8%) |
|
Abbreviations: N = number of patients in the modified intent-to-treat population; n = number of events; CRNM = clinically relevant non-major |
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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.
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
Skin and subcutaneous tissue disorders: urticaria
DRUG INTERACTIONS
Anticoagulants, Antiplatelets, Thrombolytics, And SSRIs/SNRIs
Co-administration of anticoagulants, antiplatelet drugs, thrombolytics and SSRIs or SNRIs may increase the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with anticoagulants, aspirin, other platelet aggregation inhibitors, and/or NSAIDs [see WARNINGS AND PRECAUTIONS].
Long-term concomitant treatment with SAVAYSA and other anticoagulants is not recommended because of increased risk of bleeding [see WARNINGS AND PRECAUTIONS]. Short term co-administration may be needed for patients transitioning to or from SAVAYSA [see DOSAGE AND ADMINISTRATION].
In clinical studies with SAVAYSA concomitant use of aspirin (low dose ≤ 100 mg/day) or thienopyridines, and NSAIDs was permitted and resulted in increased rates of Clinically Relevant Bleeding. Carefully monitor for bleeding in patients who require chronic treatment with low dose aspirin and/or NSAIDs [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
As with other anticoagulants the possibility may exist that patients are at an increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets [see WARNINGS AND PRECAUTIONS].
P-gp Inducers
Avoid the concomitant use of SAVAYSA with rifampin [see CLINICAL PHARMACOLOGY].
P-gp Inhibitors
Treatment Of NVAF
Based on clinical experience from the ENGAGE AF-TIMI 48 study, dose reduction in patients concomitantly receiving P-gp inhibitors resulted in edoxaban blood levels that were lower than in patients who were given the full dose. Consequently, no dose reduction is recommended for concomitant P-gp inhibitor use [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY, and Clinical Studies].
Treatment Of Deep Vein Thrombosis And Pulmonary Embolism
[see Clinical Studies]
Read the entire FDA prescribing information for Savaysa (Edoxaban Tablets)
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