Dosage & Administration
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Savaysa Prescribing Information
A. REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLATION PATIENTS WITH CRCL > 95 ML/MIN
SAVAYSA should not be used in patients with CrCL > 95 mL/min. In the ENGAGE AF-TIMI 48 study, nonvalvular atrial fibrillation patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with SAVAYSA 60 mg once daily compared to patients treated with warfarin. In these patients another anticoagulant should be used [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Clinical Studies (14.1)].
B. PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE RISK OF ISCHEMIC EVENTS
Premature 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 [see Dosage and Administration (2.4), Warnings and Precautions (5.2), and Clinical Studies (14.1)].
C. SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas may occur in patients treated with SAVAYSA who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:
- use of indwelling epidural catheters
- concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
- a history of traumatic or repeated epidural or spinal punctures
- a history of spinal deformity or spinal surgery
- optimal timing between the administration of SAVAYSA and neuraxial procedures is not known
[see Warnings and Precautions (5.4)].
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions (5.4)].
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated [see Warnings and Precautions (5.4)].
Reduction in the Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
SAVAYSA is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).
Limitation of Use for NVAF
SAVAYSA should not be used in patients with CrCL > 95 mL/min because of an increased risk of ischemic stroke compared to warfarin [see Dosage and Administration (2.1), Warnings and Precautions (5.1) and Clinical Studies (14.1)].
Treatment of Deep Vein Thrombosis and Pulmonary Embolism
SAVAYSA 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.
Nonvalvular Atrial Fibrillation
The recommended dose of SAVAYSA is 60 mg taken orally once daily [see Warnings and Precautions (5.1) and Clinical Studies (14.1)]. Assess creatinine clearance, as calculated using the Cockcroft-Gault equation 1, 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 [see Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
- 1
- Cockcroft-Gault CrCL = (140-age) × (weight in kg) × (0.85 if female) / (72 × creatinine in mg/dL).
Treatment of Deep Vein Thrombosis and Pulmonary Embolism
The recommended dose of SAVAYSA is 60 mg taken orally once daily following 5 to 10 days of initial therapy with a parenteral anticoagulant [see Clinical Studies (14.2)].
Reduce SAVAYSA dose to 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 [see Clinical Studies (14.2)].
Administration Information
If 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 [see Clinical Pharmacology (12.3)].
Transition to or from 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 |
| From | To | Recommendation |
|---|---|---|
| Abbreviations: INR=International Normalized Ratio | ||
| SAVAYSA | Warfarin | Oral option: For patients taking 60 mg 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 |
Discontinuation for Surgery and Other Interventions
Discontinue SAVAYSA at least 24 hours before invasive or surgical procedures because of the risk of bleeding [see Warnings and Precautions (5.3)].
If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention [see Warnings and Precautions (5.3)].
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 [see Warnings and Precautions (5.2)]. Administer a parenteral anticoagulant and then switch to oral SAVAYSA, if oral medication cannot be taken during or after surgical intervention.
Administration Options
For 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 [see Clinical Pharmacology (12.3)].
- 60 mg, yellow round shaped, film-coated tablets, debossed with DSC L60 on one side
- 30 mg, pink round shaped, film-coated tablets, debossed with DSC L30 on one side
- 15 mg, orange round shaped, film-coated tablets, debossed with DSC L15 on one side
Pregnancy
Risk Summary
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 Considerations
Disease-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 [see Warnings and Precautions (5.3)].
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 [see Warnings and Precautions (5.3)].
Data
Animal 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 Summary
There 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.
Females and Males of Reproductive Potential
Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.
The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including SAVAYSA should be assessed in females of reproductive potential and those with abnormal uterine bleeding.
Pediatric Use
The safety and effectiveness of SAVAYSA have not been established in pediatric patients with confirmed VTE (PE and/or DVT). Effectiveness was not demonstrated in an adequate and well-controlled study conducted in 145 SAVAYSA-treated pediatric patients, from birth to less than 18 years of age with confirmed VTE (PE and/or DVT), treated for 3 months up to a maximum of 12 months.
Geriatric Use
Of 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 the Hokusai VTE Cancer Study, 539 (52%) patients were 65 years and older and 176 (17%) 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 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].
Renal Impairment
Renal 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 [see Dosage and Administration (2.1, 2.2) and Clinical Pharmacology (12.3)].
As renal function improves and edoxaban blood levels decrease, the risk for ischemic stroke increases in patients with NVAF [see Indications and Usage (1.1), Dosage and Administration (2.1), and Clinical Studies (14.1)].
Hepatic Impairment
The 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) [see Clinical Pharmacology (12.3)].
Low Body Weight Consideration for Patients Treated for DVT and/or PE
Based 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 [see Dosage and Administration (2.2) and Clinical Studies (14.2)].
SAVAYSA is contraindicated in patients with:
- Active pathological bleeding [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].