Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

SAVAYSA (NDA-206316)

(EDOXABAN TOSYLATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/18/2023 (SUPPL-19)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Newly added information:

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Additions and revisions underlined:

SAVAYSA is a prescription medicine used to:

• reduce the risk of stroke and blood clots in people who have atrial fibrillation not caused by a heart valve problem (nonvalvular atrial fibrillation).

• treat blood clots in the veins of your legs (deep vein thrombosis) or lungs (pulmonary embolism), after you have been treated with an injectable blood thinner medicine for 5 to 10 days.

It is not known if SAVAYSA is safe and effective in children with known deep vein thrombosis or pulmonary embolism.

09/11/2023 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and revisions underlined:

The following adverse reactions have been identified during post-approval use of SAVAYSA.

Renal and urinary disorders: anticoagulant-related nephropathy

11/01/2021 (SUPPL-18)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Before taking SAVAYSA, tell your doctor about all of your medical conditions, including if you:

Additions and/or revisions underlined:

are pregnant or plan to become pregnant. It is not known if SAVAYSA will harm your unborn baby. Tell your doctor right away if you become pregnant during treatment with SAVAYSA.

Females who are able to become pregnant: Talk with your healthcare provider about pregnancy planning during treatment with SAVAYSA. Talk with your healthcare provider about your risk for severe uterine bleeding if you are treated with blood thinner medicines, including SAVAYSA.

04/20/2021 (SUPPL-17)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(Newly Added Subsection)

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.

04/21/2020 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.6 Increase Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome

Direct-acting oral anticoagulants (DOACs), including SAVAYSA, are not recommended for use in patients with triple positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin antibodies, ant anti-beta 2-glycoprotein I antibodies], treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Gastrointestinal disorders: abdominal pain

Nervous system disorders: dizziness, headache

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about SAVAYSA?

SAVAYSA is not for use in people with antiphospholipid syndrome (APS), especially with positive triple antibody testing, who have a history of blood clots.

Before taking SAVAYSA, tell your doctor about all of your medical conditions, including if you:

have antiphospholipid syndrome

08/09/2019 (SUPPL-15)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to labeling)

6.2 Postmarketing Experience

(Newly Added Subsection)

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. Immune system disorders: angioedema, hypersensitivity. Skin and subcutaneous tissue disorders: urticaria

(Additions and/or revisions are underlined)

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
Risk of Bleeding

7 Drug Interactions

7.1 Anticoagulants, Antiplatelets, Thrombolytics, and SSRIs/SNRIs

(Additions and/or revisions are underlined)

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. 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 less than or equal to 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.

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions are underlined)

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17. PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

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 with 2 to 3 ounces of water before administering immediately via the gastric feeding tube.
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.

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.

Medication Guide

(Extensive changes; please refer to labeling)

09/29/2017 (SUPPL-12)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

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.

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.

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.

Data

Animal Data

…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… 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)…

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Advise patients of the following:

to not breastfeed if they are taking SAVAYSA
for patients who cannot swallow the tablet whole, crush SAVAYSA and combine with 2 to 3 ounces of water or applesauce and ingest immediately.
for patients who require a gastric tube, crush the SAVAYSA tablet and mix it with 2 to 3 ounces of water before administering immediately via the gastric feeding tube.

MEDICATION GUIDE

(Additions and/or revisions are underlined)

How should I take SAVAYSA?

If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take SAVAYSA.

09/15/2016 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

Risk of Bleeding (updated)

SAVAYSA 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 Effect

There 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

For all people who take SAVAYSA (updated)

You may have a higher risk of bleeding if you take SAVAYSA and take other

medicines that increase your risk of bleeding, including:

selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine

reuptake inhibitors (SNRIs) (added)