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.

BYETTA (NDA-021773)

(EXENATIDE SYNTHETIC)

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

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05/28/2025 (SUPPL-50)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.4 Acute Kidney Injury Due to Volume Depletion

There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists, BYETTA [see Adverse Reactions (6.2)]. The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions (6)].

Monitor renal function in patients reporting adverse reactions to BYETTA that could lead to volume depletion, especially during dosage initiation and escalation of BYETTA.

BYETTA is not recommended in patients with severe renal impairment (creatinine clearance

<30 mL/min) or end-stage renal disease and should be used with caution in patients with renal transplantation [see Use in Specific Populations (8.6)].

5.5 Severe Gastrointestinal Adverse Reactions

Use of GLP-1 receptor agonists, including BYETTA, has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6)]. BYETTA is not recommended in patients with severe gastroparesis.

6 Adverse Reactions

Additions and/or revisions underlined:

…

Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions (5.4)]

Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.5)]

…

6.2 Postmarketing Experience

…

Hypersensitivity: Injection-site reactions generalized pruritus and/or urticaria, macular or papular rash, angioedema, anaphylactic reaction.

Neurologic: Dysgeusia, somnolence, dysesthesia.

…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Acute Kidney Injury Due to Volume Depletion

Inform patients of the potential risk of acute kidney injury due to dehydration associated with gastrointestinal adverse reactions. Advise patients to take precautions to avoid fluid depletion. Inform patients of the signs and symptoms of acute kidney injury and instruct them to promptly report any of these signs or symptoms or persistent (or extended) nausea, vomiting, and diarrhea to their healthcare provider [see Warnings and Precautions (5.4)].

Severe Gastrointestinal Adverse Reactions

Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms [see Warnings and Precautions (5.5)].

…

MEDICATION GUIDE

Extensive additions and/or revisions, please refer to label for complete information.

11/01/2024 (SUPPL-49)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Pulmonary Aspiration During General Anesthesia or Deep Sedation

Newly added subsection:

BYETTA delays gastric emptying [see Clinical Pharmacology (12.2)]. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations.

Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking BYETTA, including whether modifying preoperative fasting recommendations or temporarily discontinuing BYETTA could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking BYETTA.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.10)]

6.2 Postmarketing Experience

Newly added information:

…

Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation.

…

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

PATIENT COUNSELING INFORMATION

Newly added information:

…

Pulmonary Aspiration During General Anesthesia or Deep Sedation

Inform patients that BYETTA may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking BYETTA [see Warnings and Precautions (5.10)].

…

MEDICATION GUIDE

Additions and/or revisions underlined:

Before taking BYETTA, tell your healthcare provider about all of your medical conditions, including if you:

…

are scheduled to have surgery or other procedures that use anesthesia or deep sleepiness (deep sedation).

…

What are the possible side effects of BYETTA?

BYETTA may cause serious side effects, including:

…

Food or liquid getting into the lungs during surgery or other procedures that use anesthesia or deep sleepiness (deep sedation). BYETTA may increase the chance of food getting into your lungs during surgery or other procedures. Tell all your healthcare providers that you are taking BYETTA before you are scheduled to have surgery or other procedures.

12/21/2022 (SUPPL-48)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and revisions underlined:

Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, ileus, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death [see Indications and Usage (1)].

06/10/2022 (SUPPL-47)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Acute Gallbladder Disease

Newly added subsection:
Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In a clinical study with exenatide, 1.9% of exenatide-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Acute Gallbladder Disease [see Warnings and Precautions (5.9)]

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Cholelithiasis and cholecystitis

In a clinical study with exenatide, 1.9% of exenatide-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis.

…

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy.

…

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Gallbladder problems. Gallbladder problems have happened in some people who take BYETTA. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include:

pain in your upper stomach (abdomen)
yellowing of skin or eyes (jaundice)
fever
clay-colored stools

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Acute Gallbladder Disease

Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up [see Warnings and Precautions (5.9)].

…

11/04/2021 (SUPPL-45)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of BYETTA have not been established in pediatric patients.

Effectiveness of BYETTA was not demonstrated in a randomized, double-blind, placebo- controlled study conducted in 120 pediatric patients (78 received BYETTA and 42 received placebo) aged 10 to 17 years with type 2 diabetes mellitus.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Acute Pancreatitis

Inform patients that persistent severe abdominal pain that may radiate to the back and which may

or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis …

06/17/2021 (SUPPL-44)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

BYETTA is contraindicated in patients with:

A prior severe hypersensitivity reaction to exenatide or to any of the excipients in BYETTA. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with BYETTA [see Warnings and Precautions (5.7)].

5 Warnings and Precautions

Additions and/or revisions underlined:

5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

Patients receiving BYETTA in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia including severe hypoglycemia [see Adverse Reactions (6) and Drug Interactions (7.2)].

The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

6 Adverse Reactions

Additions and/or revisions underlined:

Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3)]

6.2 Postmarketing Experience

Metabolic: Severe hypoglycemia with concomitant use of sulfonylurea or insulin

Neurologic: dysgeusia; somnolence

7 Drug Interactions

Newly added subsection:

7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

When initiating BYETTA, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3) and Adverse Reactions (6)].

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see Clinical Pharmacology (12.3)]. BYETTA was studied in 282 patients 65 years of age or older …

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

Inform patients that the risk of hypoglycemia is increased when BYETTA is used in combination with an agent that induces hypoglycemia, such as a sulfonylurea or insulin. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.3)].

Acute Kidney Injury

Inform patients treated with BYETTA of the potential risk for worsening renal function …

02/28/2020 (SUPPL-43)

Approved Drug Label (PDF)

4 Contraindications

Addition of the following bullet point underlined:

BYETTA is contraindicated in patients with:

A history of drug-induced immune-mediated thrombocytopenia from exenatide products. Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported with exenatide use [see Warnings and Precautions (5.8)].

5 Warnings and Precautions

Additions and/or revisions underlined:

5.4 Acute Kidney Injury

… Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including BYETTA. Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.

BYETTA is not recommended in patients with severe renal impairment (creatinine clearance

<30 mL/min) or end-stage renal disease and should be used with caution in patients with renal transplantation [see Use in Specific Populations (8.6)]. Because BYETTA may induce nausea and vomiting with transient hypovolemia, treatment may worsen renal function. Caution should be applied when initiating or escalating doses of BYETTA from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min).

5.7 Hypersensitivity

There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) in patients treated with BYETTA. If a hypersensitivity reaction occurs, the patient should discontinue BYETTA and other suspect medications and promptly seek medical advice. Inform and closely monitor patients with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist for allergic reactions, because it is unknown whether such patients will be predisposed to anaphylaxis with BYETTA [see Adverse Reactions (6.2)].

Newly added subsection:

5.8 Drug-Induced Thrombocytopenia

Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported in the postmarketing setting with exenatide use. Drug-induced thrombocytopenia is an immune-mediated reaction, with exenatide-dependent anti-platelet antibodies. In the presence of exenatide, these antibodies cause platelet destruction. If drug-induced thrombocytopenia is suspected, discontinue BYETTA immediately and do not re-expose the patient to exenatide [see Adverse Reactions (6.2)].

6 Adverse Reactions

Addition of the following bulleted line listings:

The following serious adverse reactions are described below or elsewhere in the prescribing information:

Never Share a BYETTA Pen Between Patients [see Warnings and Precautions (5.1)]
Acute Pancreatitis [see Warnings and Precautions (5.2)]
Hypoglycemia [see Warnings and Precautions (5.3)]
Acute Kidney Injury [see Warnings and Precautions (5.4)]
Gastrointestinal Disease [see Warnings and Precautions (5.5)]
Immunogenicity [see Warnings and Precautions (5.6)]
Hypersensitivity [see Warnings and Precautions (5.7)]
Drug-Induced Thrombocytopenia [see Warnings and Precautions (5.8)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following additional adverse reactions have been reported during postapproval use of BYETTA or other exenatide formulations. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic Systems: drug-induced thrombocytopenia [see Warnings and Precautions (5.8)].

8 Use in Specific Populations

8.6 Renal Impairment

Additions and/or revisions underlined:

BYETTA is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min) and should be used with caution in patients with renal transplantation. In patients with end-stage renal disease receiving dialysis, single doses of BYETTA 5 mcg were not well-tolerated due to gastrointestinal side effects.

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

MEDICATION GUIDE

Who should not use BYETTA?

Do not use BYETTA if:

Addition of the following second bullet point underlined:

you have a history of low blood platelet count from using exenatide medicines (drug-induced thrombocytopenia).

What are the possible side effects of BYETTA?

BYETTA may cause serious side effects, including:

Newly added bullet point:

BYETTA causes stomach problems or will cause your stomach problems to worsen.

Low blood platelet count (drug-induced thrombocytopenia). BYETTA may cause the number of platelets in your blood to be reduced. When your platelet count is too low, your body cannot form blood clots. You could have serious bleeding that could lead to death. Stop using BYETTA and call your healthcare provider right away if you have unusual bleeding or bruising.

PATIENT COUNSELING INFORMATION

Newly added information:

Risk of Drug-Induced Thrombocytopenia

Inform patients that drug-induced immune-mediated thrombocytopenia has been reported during

use of exenatide. Inform patients that if symptoms of thrombocytopenia occur, stop taking

BYETTA and seek medical advice promptly [see Warnings and Precautions (5.8)].

12/20/2018 (SUPPL-41)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Extensive changes – please refer to labeling)

8.2 Lactation

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

Risk Summary

There is no information regarding the presence of BYETTA, in human milk, the effects of BYETTA on the breastfed infant, or the effects of BYETTA on milk production. Exenatide was present in the milk of lactating mice. However, due to species-specific differences in lactation physiology, the clinical relevance of these data is not clear. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BYETTA and any potential adverse effects on the breastfed child from BYETTA or from the underlying maternal condition.

Data

In lactating mice subcutaneously injected twice a day with exenatide, the concentration of exenatide in milk was up to 2.5% of the concentration in maternal plasma.