A specific reversal agent for edoxaban is not available. Overdose of SAVAYSA increases the risk of bleeding.
The following are not expected to reverse the anticoagulant effects of edoxaban: protamine sulfate, vitamin K, and tranexamic acid.
Hemodialysis does not significantly contribute to edoxaban clearance.
SAVAYSA is contraindicated in patients with:
The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information.
The most serious adverse reactions reported with SAVAYSA were related to bleeding.
Clinical Trials ExperienceBecause 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.
The ENGAGE AF-TIMI 48 StudyIn 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 ≤ 95mL/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. |
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) |
| 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 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 |
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 ReactionsThe 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 StudyIn 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 StudyThe 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
| SAVAYSA (N=4118) |
Warfarin (N=4122) |
|
| Clinically Relevant Bleeding (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 (%) |
Warfarin (N=4122) n (%) |
|
| Bleeding ADRsa | ||
| Vaginalb | 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) |
| 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 |
||
SAVAYSA is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).
Limitation Of Use For NVAFSAVAYSA should not be used in patients with CrCL > 95 mL/min because of an increased risk of ischemic stroke compared to warfarin.
Treatment Of Deep Vein Thrombosis And Pulmonary EmbolismSAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.
As a result of FXa inhibition, edoxaban prolongs clotting time tests such as prothrombin time (PT), and activated partial thromboplastin time (aPTT). Changes observed in PT, INR, and aPTT at the expected therapeutic dose, however, are small, subject to a high degree of variability and not useful in monitoring the anticoagulant effect of edoxaban. Following oral administration, peak pharmacodynamic effects are observed within 1-2 hours, which correspond with peak edoxaban concentrations (Cmax).
Cardiac ElectrophysiologyIn a thorough QT study in healthy men and women aged 19-45 years, no QTc interval prolongation was observed with edoxaban (90 mg and 180 mg).
Effect Of PCCs On Pharmacodynamics Of SAVAYSAThere is no systematic evaluation of bleeding reversal by 4-factor prothrombin complex concentrate (PCC) products in patients who have received SAVAYSA.
Effects of PCC (50 IU/kg) on the pharmacodynamics of edoxaban were studied in healthy subjects following a punch biopsy. Following administration of a single dose of edoxaban, endogenous thrombin potential (ETP) returned to pre-edoxaban baseline levels in 0.5 hours after the initiation of a 15 minute infusion of 50 IU/kg PCC, compared to more than 24 hours with placebo. Mean ETP levels continued to increase and exceeded pre-edoxaban baseline, reaching maximum elevations (~40% over pre-edoxaban levels) at 22 hours after initiating PCC dose, which was the last observation of ETP. The clinical relevance of this ETP increase is unknown.
Pharmacodynamic InteractionsAspirin
Co-administration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
NSAID (Naproxen)
Co-administration of naproxen (500 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Edoxaban displays approximately dose-proportional pharmacokinetics for doses of 15 to 150 mg and 60 to 120 mg following single and repeat doses, respectively, in healthy subjects.
AbsorptionFollowing oral administration, peak plasma edoxaban concentrations are observed within 1-2 hours. Absolute bioavailability is 62%. Food does not affect total systemic exposure to edoxaban. SAVAYSA was administered with or without food in the ENGAGE AF-TIMI 48 and Hokusai VTE trials.
Administration of a crushed 60 mg tablet, either mixed into applesauce or suspended in water and given through a nasogastric tube, showed similar exposure compared to administration of an intact tablet.
DistributionDisposition is biphasic. The steady-state volume of distribution (Vdss) is 107 (19.9) L [mean (SD)]. In vitro plasma protein binding is approximately 55%. There is no clinically relevant accumulation of edoxaban (accumulation ratio 1.14) with once daily dosing.
Steady-state concentrations are achieved within 3 days.
MetabolismUnchanged edoxaban is the predominant form in plasma. There is minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation, and oxidation by CYP3A4.
The predominant metabolite M-4, formed by hydrolysis, is human-specific and active and reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5% of exposure to edoxaban.
EliminationEdoxaban is eliminated primarily as unchanged drug in the urine. Renal clearance (11 L/hour) accounts for approximately 50% of the total clearance of edoxaban (22 L/hour). Metabolism and biliary/intestinal excretion account for the remaining clearance. The terminal elimination half-life of edoxaban following oral administration is 10 to 14 hours.
Available data about SAVAYSA use in pregnant women are insufficient to determine whether there are drug-associated risks for adverse developmental outcomes. In animal developmental studies, no adverse developmental effects were seen when edoxaban was administered orally to pregnant rats and rabbits during organogenesis at up to 16-times and 8-times, respectively, the human exposure, when based on body surface area and AUC, respectively (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical ConsiderationsDisease-Associated Maternal And/Or Embryo/Fetal Risk
Pregnancy confers an increased risk of thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions. Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy.
Fetal/Neonatal Adverse Reactions
Use of anticoagulants, including edoxaban, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding.
Labor Or Delivery
All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. SAVAYSA use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider use of a shorter acting anticoagulant as delivery approaches ].
DataAnimal Data
Embryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no malformation was seen when edoxaban was administered orally at doses up to 300 mg/kg/day, or 49 times the human dose of 60 mg/day normalized to body surface area. Increased post-implantation loss occurred at 300 mg/kg/day, but this effect may be secondary to the maternal vaginal hemorrhage seen at this dose. In rabbits, no malformation was seen at doses up to 600 mg/kg/day (49 times the human exposure at a dose of 60 mg/day when based on AUC). Embryo-fetal toxicities occurred at maternally toxic doses, and included absent or small fetal gallbladder at 600 mg/kg/day, and increased post-implantation loss, increased spontaneous abortion, and decreased live fetuses and fetal weight at doses equal to or greater than 200 mg/kg/day, which is equal to or greater than 20 times the human exposure.
In a rat pre-and post-natal developmental study, edoxaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 30 mg/kg/day, which is up to 3 times the human exposure when based on AUC. Vaginal bleeding in pregnant rats and delayed avoidance response (a learning test) in female offspring were seen at 30 mg/kg/day.
SAVAYSA (edoxaban) is supplied as round shaped, film-coated, non-scored tablets containing edoxaban tosylate equivalent to 60, 30 or 15 mg of SAVAYSA, packaged in bottles and blisters.
| Strength | Color | Deboss | NDC 65597-xxx-yy | |||||
| xxx | yy | |||||||
| Bottle of | Blister of | |||||||
| 30 | 90 | 500 | 10 x 10* | 10 x 5** | ||||
| 15 mg | orange | DSC L15 | 201 | 30 | - | - | - | - |
| 30 mg | pink | DSC L30 | 202 | 30 | 90 | 50 | 10 | 05 |
| 60 mg | yellow | DSC L60 | 203 | 30 | 90 | 50 | 10 | 05 |
| *10 blister cards of 10 counts **5 blister cards of 10 counts |
Store at 20-25°C (68-77°F); excursions permitted to 15°-30°C (59°-86°F).
Keep out of the reach of children.
Manufactured by: Daiichi Sankyo Co., LTD. Tokyo 103-8426 Japan Distributed by: Daiichi Sankyo, Inc. Parsippany, NJ 07054 USA. Â Revised: Sep 2017
Included as part of the PRECAUTIONS section.
PRECAUTIONS Reduced Efficacy In Nonvalvular Atrial Fibrillation Patients With CrCL > 95 mL/minSAVAYSA should not be used in patients with CrCL > 95 mL/min. In the randomized ENGAGE AF-TIMI 48 study, NVAF patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with SAVAYSA 60 mg daily compared to patients treated with warfarin. In these patients another anticoagulant should be used.
Increased Risk Of Stroke With Discontinuation of SAVAYSA in Patients with Nonvalvular Atrial FibrillationPremature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If SAVAYSA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant as described in the transition guidance.
Risk Of BleedingSAVAYSA 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 and serotonin norepinephrine reuptake inhibitors.
Reversal Of Anticoagulant EffectThere 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. 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. 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.
Spinal/Epidural Anesthesia Or PunctureWhen 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 12 hours after the last administration of SAVAYSA. The next dose of SAVAYSA should not be administered earlier than 2 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture.
Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, 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.
Patients With Mechanical Heart Valves Or Moderate To Severe Mitral StenosisThe safety and efficacy of SAVAYSA has not been studied in patients with mechanical heart valves or moderate to severe mitral stenosis. The use of SAVAYSA is not recommended in these patients.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide).
Advise patients of the following:
Edoxaban was not carcinogenic when administered daily to mice and rats by oral gavage for up to 104 weeks. The highest dose tested (500 mg/kg/day) in male and female mice was 3 and 6 times, respectively, the human exposure (AUC) at the human dose of 60 mg/day, and the highest doses tested in male (600/400 mg/kg/day) and female (200 mg/kg/day) rats were 8 and 14 times, respectively, the human exposure at the human dose of 60 mg/day.
Edoxaban and its human-specific metabolite, M-4, were genotoxic in in vitro chromosomal aberration tests but were not genotoxic in the in vitro bacterial reverse mutation (Ames test), in in vitro human lymphocytes micronucleus test, in in vivo rat bone marrow micronucleus test, in in vivo rat liver micronucleus test, and in in vivo unscheduled DNA synthesis tests.
Edoxaban showed no effects on fertility and early embryonic development in rats at doses of up to 1000 mg/kg/day (162 times the human dose of 60 mg/day normalized to body surface area).
Use In Specific Populations Pregnancy Risk SummaryAvailable data about SAVAYSA use in pregnant women are insufficient to determine whether there are drug-associated risks for adverse developmental outcomes. In animal developmental studies, no adverse developmental effects were seen when edoxaban was administered orally to pregnant rats and rabbits during organogenesis at up to 16-times and 8-times, respectively, the human exposure, when based on body surface area and AUC, respectively (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical ConsiderationsDisease-Associated Maternal And/Or Embryo/Fetal Risk
Pregnancy confers an increased risk of thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions. Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy.
Fetal/Neonatal Adverse Reactions
Use of anticoagulants, including edoxaban, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding.
Labor Or Delivery
All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. SAVAYSA use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider use of a shorter acting anticoagulant as delivery approaches ].
DataAnimal Data
Embryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no malformation was seen when edoxaban was administered orally at doses up to 300 mg/kg/day, or 49 times the human dose of 60 mg/day normalized to body surface area. Increased post-implantation loss occurred at 300 mg/kg/day, but this effect may be secondary to the maternal vaginal hemorrhage seen at this dose. In rabbits, no malformation was seen at doses up to 600 mg/kg/day (49 times the human exposure at a dose of 60 mg/day when based on AUC). Embryo-fetal toxicities occurred at maternally toxic doses, and included absent or small fetal gallbladder at 600 mg/kg/day, and increased post-implantation loss, increased spontaneous abortion, and decreased live fetuses and fetal weight at doses equal to or greater than 200 mg/kg/day, which is equal to or greater than 20 times the human exposure.
In a rat pre-and post-natal developmental study, edoxaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 30 mg/kg/day, which is up to 3 times the human exposure when based on AUC. Vaginal bleeding in pregnant rats and delayed avoidance response (a learning test) in female offspring were seen at 30 mg/kg/day.
Lactation Risk SummaryThere are no data on the presence of edoxaban in human milk, or its effects on the breastfeeding infant or on milk production. Edoxaban was present in rat milk. Because of the potential for serious adverse reactions in nursing infants, including hemorrhage, advise patients that breastfeeding is not recommended during treatment with SAVAYSA.
Pediatric UseSafety and effectiveness in pediatric patients have not been established.
Geriatric UseOf the total patients in the ENGAGE AF-TIMI 48 study, 5182 (74%) were 65 years and older, while 2838 (41%) were 75 years and older. In Hokusai VTE, 1334 (32%) patients were 65 years and older, while 560 (14%) patients were 75 years and older. In clinical trials the efficacy and safety of SAVAYSA in elderly (65 years or older) and younger patients were similar.
Renal ImpairmentRenal clearance accounts for approximately 50% of the total clearance of edoxaban. Consequently, edoxaban blood levels are increased in patients with poor renal function compared to those with higher renal function. Reduce SAVAYSA dose to 30 mg once daily in patients with CrCL 15-50 mL/min. There are limited clinical data with SAVAYSA in patients with CrCL < 15 mL/min; SAVAYSA is therefore not recommended in these patients. Hemodialysis does not significantly contribute to SAVAYSA clearance.
As renal function improves and edoxaban blood levels decrease, the risk for ischemic stroke increases in patients with NVAF.
Hepatic ImpairmentThe use of SAVAYSA in patients with moderate or severe hepatic impairment (Child-Pugh B and C) is not recommended as these patients may have intrinsic coagulation abnormalities. No dose reduction is required in patients with mild hepatic impairment (Child-Pugh A).
Low Body Weight Consideration For Patients Treated For DVT And/Or PEBased on the clinical experience from the Hokusai VTE study, reduce SAVAYSA dose to 30 mg in patients with body weight less than or equal to 60 kg.
The recommended dose of SAVAYSA is 60 mg taken orally once daily. Assess creatinine clearance, as calculated using the Cockcroft-Gault equation*, before initiating therapy with SAVAYSA. Do not use SAVAYSA in patients with CrCL > 95 mL/min.
Reduce SAVAYSA dose to 30 mg once daily in patients with CrCL 15 to 50 mL/min.
*Cockcroft-Gault CrCL = (140-age) x (weight in kg) x (0.85 if female) / (72 x creatinine in mg/dL).
Treatment Of Deep Vein Thrombosis And Pulmonary EmbolismThe recommended dose of SAVAYSA is 60 mg taken orally once daily following 5 to 10 days of initial therapy with a parenteral anticoagulant.
The recommended dose of SAVAYSA is 30 mg once daily in patients with CrCL 15 to 50 mL/min, patients who weigh less than or equal to 60 kg, or patients who are taking certain concomitant P-gp inhibitor medications based on clinical study data in this indication.
Administration InformationIf a dose of SAVAYSA is missed, the dose should be taken as soon as possible on the same day. Dosing should resume the next day according to the normal dosing schedule. The dose should not be doubled to make up for a missed dose.
SAVAYSA can be taken without regard to food.
Transition To Or From SAVAYSATransition To SAVAYSA
| From | To | Recommendation |
| Warfarin or other Vitamin K Antagonists | SAVAYSA | Discontinue warfarin and start SAVAYSA when the INR is ≤ 2.5 |
| Oral anticoagulants other than warfarin or other Vitamin K Antagonists | SAVAYSA | Discontinue current oral anticoagulant and start SAVAYSA at the time of the next scheduled dose of the other oral anticoagulant |
| Low Molecular Weight Heparin (LMWH) | SAVAYSA | Discontinue LMWH and start SAVAYSA at the time of the next scheduled administration of LMWH |
| Unfractionated heparin | SAVAYSA | Discontinue the infusion and start SAVAYSA 4 hours later |
Transition from SAVAYSA
| From | To | Recommendation |
| SAVAYSA | Warfarin | Oral option: For patients taking 60 ms of SAVAYSA, reduce the dose to 30 mg and begin warfarin concomitantly. For patients receiving 30 mg of SAVAYSA, reduce the dose to 15 mg and begin warfarin concomitantly. INR must be measured at least weekly and just prior to the daily dose of SAVAYSA to minimize the influence of SAVAYSA on INR measurements. Once a stable INR ≥ 2.0 is achieved, SAVAYSA should be discontinued and the warfarin continued |
| SAVAYSA | Warfarin | Parenteral option: Discontinue SAVAYSA and administer a parenteral anticoagulant and warfarin at the time of the next scheduled SAVAYSA dose. Once a stable INR ≥ 2.0 is achieved the parenteral anticoagulant should be discontinued and the warfarin continued |
| SAVAYSA | Non-Vitamin-K-Dependent Oral anticoagulants | Discontinue SAVAYSA and start the other oral anticoagulant at the time of the next dose of SAVAYSA |
| SAVAYSA | Parenteral anticoagulants | Discontinue SAVAYSA and start the parenteral anticoagulant at the time of the next dose of SAVAYSA |
| Abbreviations: INR=International Normalized Ratio |
Discontinue SAVAYSA at least 24 hours before invasive or surgical procedures because of the risk of bleeding.
If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.
SAVAYSA can be restarted after the surgical or other procedure as soon as adequate hemostasis has been established noting that the time to onset of pharmacodynamic effect is 1-2 hours. Administer a parenteral anticoagulant and then switch to oral SAVAYSA, if oral medication cannot be taken during or after surgical intervention.
Administration OptionsFor patients who are unable to swallow whole tablets, SAVAYSA tablets may be crushed and mixed with 2 to 3 ounces of water and immediately administered by mouth or through a gastric tube. The crushed tablets may also be mixed into applesauce and immediately administered orally.
In vitro studies indicate that edoxaban does not inhibit the major cytochrome P450 enzymes (CYP1A2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, or 3A4) and does not induce CYP1A2, CYP3A4 or the P-gp transporter (MDR1). In vitro data also indicate that edoxaban does not inhibit the following transporters at clinically relevant concentrations: P-gp, the organic anion transporters OAT1 or OAT3; the organic cation transporters OCT1 or OCT2; or the organic ion transporting polypeptides OATP1B1 or OATP1B3. Edoxaban is a substrate of P-gp transporter.
Impact Of Other Drugs On SAVAYSAThe effect of co-administered amiodarone, cyclosporine, dronedarone, erythromycin, ketoconazole, quinidine, verapamil, and rifampin on edoxaban exposure is shown in Figure 12.1.
Figure 12.1: Summary of Drug Interaction Study Results
Edoxaban increased the Cmax of concomitantly administered digoxin by 28%; however, the AUC was not affected. Edoxaban had no effect on the Cmax and AUC of quinidine.
Edoxaban decreased the Cmax and AUC of concomitantly administered verapamil by 14% and 16%, respectively.
