DRUG INTERACTIONS

1. 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

 Long-term concomitant treatment with SAVAYSA and other anticoagulants is not recommended because of increased risk of bleeding [see

 Short term co-administration may be needed for patients transitioning to or from SAVAYSA

 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

 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

2 P-gp Inducers Avoid the concomitant use of SAVAYSA with rifampin

3 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 

Treatment of Deep Vein Thrombosis and Pulmonary Embolism

BRIEF SUMMARY

ENDOXAN TABLETS- (Apr 2015)

Indn-      To reduce the risk of stroke and system Embolism (SE) in patients with Non-valvular  Atrial Fibralilation (NVAF)

Comp-    • Tablets: 60 mg, 30 mg, and 15 mg                                                                      The recommended dose is 60 mg once daily in patients with CrCL >50 to = 95 mL/min. Do not use  in patients with CrCL > 95 mL/min (2.1) Reduce dose to 30 mg once daily in patients with creatinine clearance 15 to 50 mL/min

ADR-     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

CI-      • Active pathological bleeding

WARNINGS -

 • Bleeding: Serious and potentially fatal bleeding. Promptly evaluate signs and symptoms of blood loss

Pat Infm-

Advise patients of the following: Instructions for Patient Use.                                             • Advise patients to take  exactly as prescribed                                                                 .• Remind patients to not discontinue  without talking to the healthcare provider who prescribed it.                                                                                                                 • Instruct patients to keep an adequate supply of tablets to ensure continuous dosing of the drug

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Novel Drug Approvals for 2015

1.Name       - SAVAYSA

2. Active Ingredient-     Endoxaban Tablets

3. Indication-      To reduce the risk of stroke and system Embolism (SE) in patients with Non-valvular Atrial Fibralilation (NVAF_

Date of Approval  Jan 2015

   HIGHLIGHTS OF PRESCRIBING INFORMATION-

 These highlights do not include all the information needed to use SAVAYSA® safely and effectively. See full prescribing information for SAVAYSA. SAVAYSA (edoxaban) tablets, for oral use

Initial U.S. Approval: 2015

WARNING:

(A) REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLATION PATIENTS WITH CREATININE CLEARANCE (CRCL) > 95 ML/MIN (B) PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE RISK OF ISCHEMIC EVENTS

(C) SPINAL/EPIDURAL HEMATOMA See full prescribing information for complete boxed warning. (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

. (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 

(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

. RECENT MAJOR CHANGES Warnings and Precautions, Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome 

 INDICATIONS AND USAGE

 SAVAYSA is a factor Xa inhibitor 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 creatinine clearance (CrCL) > 95 mL/min because of increased risk of ischemic stroke compared to warfarin at the highest dose studied (60 mg)

 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 

ADVERSE REACTIONS -

 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

  CONTRAINDICATIONS-

 • Active pathological bleeding

WARNINGS AND PRECAUTIONS-

 • Bleeding: Serious and potentially fatal bleeding. Promptly evaluate signs and symptoms of blood loss

 • Mechanical heart valves or moderate to severe mitral stenosis: Use is not recommended

 DOSAGE AND ADMINISTRATION-

 • Treatment of NVAF: Assess CrCL before initiating therapy

 The recommended dose is 60 mg once daily in patients with CrCL >50 to = 95 mL/min. Do not use SAVAYSA in patients with CrCL > 95 mL/min (2.1) Reduce dose to 30 mg once daily in patients with creatinine clearance 15 to 50 mL/min

 • Treatment of DVT and PE: The recommended dose is 60 mg once daily (2.2) The recommended dose is 30 mg once daily for patients with CrCL 15 to 50 mL/min or body weight less than or equal to 60 kg or who use certain P-gp inhibitors

 DOSAGE FORMS AND STRENGTHS-

 • Tablets: 60 mg, 30 mg, and 15 mg

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Advise patients of the following: Instructions for Patient Use

• Advise patients to take SAVAYSA exactly as prescribed.

• Remind patients to not discontinue SAVAYSA without talking to the healthcare provider who prescribed it.

• Instruct patients to keep an adequate supply of tablets to ensure continuous dosing of SAVAYSA.

• Instruct patients who cannot swallow the tablet whole to crush SAVAYSA, combine with 2 to 3 ounces of water or applesauce and ingest immediately.

• Instruct patients who require a gastric tube to crush the SAVAYSA tablet and mix it ube.with 2 to 3 ounces of water before administering immediately via the gastric feeding 

• Inform patients that if a dose is missed, they should take SAVAYSA as soon as possible the same day, and resume the normal dosing schedule the following day. The dose should not be doubled to make up for a missing dose.

Bleeding Risk • Advise patients that they may bleed more easily, may bleed longer, or bruise more easily when treated with SAVAYSA.

• Instruct patients to report any unusual bleeding immediately to their healthcare provider. 

• For patients that are having neuraxial anesthesia or spinal puncture, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence.

If any of these symptoms occur, advise the patient to contact his or her physician immediately [see Boxed Warning].

Invasive or Surgical Procedures

• Remind patients to inform their healthcare providers that they are taking SAVAYSA before any surgery, medical, or dental procedure is scheduled. Concomitant Medication and Herbals

• Remind patients to inform their healthcare providers and dentists if they plan to take, or are taking any prescription medications, over-the-counter drugs or herbal products. Pregnancy

• Remind patients to inform their healthcare provider immediately if they become pregnant or intend to become pregnant during treatment with SAVAYSA.

• Inform patients to not breastfeed if they are taking SAVAYSA

Manufactured by: Daiichi Sankyo Co., LTD. Tokyo 103-8426 Japan Distributed by: Daiichi Sankyo, Inc. Basking Ridge, NJ 07920-2311 USA SAVAYSA® is a trademark of Daiichi Sankyo Co., LTD. Copyright © 2021, Daiichi Sankyo, Inc. USPI-SAV-C8-0321-r102

CLINICAL PHARMACOLOGY

1. Mechanism of Action Edoxaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity.

Edoxaban inhibits free FXa, and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of FXa in the coagulation cascade reduces thrombin generation and reduces thrombus formation.

2. Pharmacodynamics -                                                                                                  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.

Cardiac Electrophysiology-                                                                                            In 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 SAVAYSA There is no systematic evaluation of bleeding reversal by 4-factor prothrombin complex concentrate (PCC) products in patients who have received SAVAYSA.

3. Pharmacokinetics-                                                                                                    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.

Absorption-                                                                                                            Following 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.

Distribution-                                                                                                               Disposition 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.

Metabolism-                                                                                                        Unchanged 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.

Elimination-                                                                                                                   Edoxaban 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.

Specific Populations-                                                                                                      Hepatic Impairment In a dedicated pharmacokinetic study, patients with mild or moderate hepatic impairment (classified as Child-Pugh A or Child-Pugh B) exhibited similar pharmacokinetics and pharmacodynamics to their matched healthy control group. There is no clinical experience with edoxaban in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].

Renal Impairment 20 Reference ID: 4781828 In a dedicated pharmacokinetic study, total systemic exposure to edoxaban for subjects with CrCL > 50 to < 80 mL/min, CrCL 30 to 50 mL/min, CrCL < 30 mL/min, or undergoing peritoneal dialysis, were increased by 32%, 74%, 72%, and 93%, respectively, relative to subjects with CrCL = 80 mL/min 

Drug Interactions-                                                                                                            In vitro Drug Interactions Studies 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).

USE IN SPECIFIC POPULATIONS

1. 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.

 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.

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].

2, 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.

3. 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.

4. Pediatric Use-                                                                                                                Safety and effectiveness in pediatric patients have not been established.

5. 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

6. 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.

 OVERDOSAGE -

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.