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.

BYDUREON BCISE (NDA-209210)

(EXENATIDE)

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

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05/28/2025 (SUPPL-25)

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, including BYDUREON BCISE [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 BYDUREON BCISE that could lead to volume depletion, especially when initiating BYDUREON BCISE.

BYDUREON BCISE is not recommended for use in patients with an eGFR below 45 mL/min/1.73 m2

[see Use in Specific Populations (8.6)].

5.5 Severe Gastrointestinal Adverse Reactions

Additions and/or revisions underlined:

Use of GLP-1 receptor agonists, including BYDUREON BCISE, has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6)]. BYDUREON BCISE 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)]
…
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
…
Acute Pancreatitis
In clinical trials of BYDUREON BCISE acute pancreatitis occurred in 0.4% of patients.
…
6.2 Postmarketing Experience
Additions and/or revisions underlined:
…
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

Additions and/or revisions underlined:

Read this Medication Guide and the Instructions for Use that comes with BYDUREON BCISE before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your

treatment. If you have questions about BYDUREON BCISE after reading this information, ask your healthcare provider or pharmacist.

…

Before using BYDUREON BCISE, tell your healthcare provider about all of your medical conditions, including if you:

…

are pregnant or plan to become pregnant. It is not known if BYDUREON BCISE will harm your unborn baby. Tell your healthcare provider if you become pregnant while using BYDUREONBCISE. Talk to your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.
…
How should I use BYDUREON BCISE?
…

Do not share your BYDUREON BCISE pen with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them.
If you take too much BYDUREON BCISE, call your healthcare provider or Poison Help line at 1-800- 222-1222 or go to the nearest hospital emergency room right away.
What are the possible side effects of BYDUREON BCISE? BYDUREON BCISE may cause serious side effects, including:
…

dehydration leading to kidney problems. Diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems. It is important for you to drink fluids to help reduce your chance of dehydration. Tell your healthcare provider right away if you have nausea, vomiting, or diarrhea that does not go away.
severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use BYDUREON BCISE. Tell your healthcare provider if you have stomach problems that are severe or will not go away.
serious allergic reactions. Stop using BYDUREON BCISE and get medical help right away if you have any symptoms of a serious allergic reaction, including
- swelling of your face, lips, tongue or throat
- fainting or feeling dizzy
- problems breathing or swallowing
- very rapid heartbeat
- severe rash or itching
  …

11/01/2024 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 Pulmonary Aspiration During General Anesthesia or Deep Sedation

Newly added subsection:

BYDUREON BCISE 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 BYDUREON BCISE, including whether modifying preoperative fasting recommendations or temporarily discontinuing BYDUREON BCISE 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 BYDUREON BCISE.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.11)]

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 BYDUREON BCISE 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 BYDUREON BCISE [see Warnings and Precautions (5.11)].

…

MEDICATION GUIDE

Additions and/or revisions underlined:

Before using BYDUREON BCISE, 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 BYDUREON BCISE?

…

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

12/21/2022 (SUPPL-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Immunogenicity-Associated Decreased Glycemic Control

Subsection title revised

Extensive changes; please refer to label

5.9 Serious Injection-Site Reactions

Subsection title revised

6 Adverse Reactions

Additions and revisions underlined:

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

Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
Acute Pancreatitis [see Warnings and Precautions (5.2)]
Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3)]
Acute Kidney Injury [see Warnings and Precautions (5.4)]
Gastrointestinal Disease [see Warnings and Precautions (5.5)]
Immunogenicity-Associated Decreased Glycemic Control [see Warnings and Precautions (5.6)]
Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
Drug-Induced Thrombocytopenia [see Warnings and Precautions (5.8)]
Serious Injection-Site Reactions [see Warnings and Precautions (5.9)]
Acute Gallbladder Disease [see Warnings and Precautions (5.10)]

6.1 Clinical Trial Experience

Additions and revisions underlined:

Injection-Site Adverse Reactions Including Nodules

In the two comparator-controlled 28-week trials in adults, injection site reactions (including injection site nodule, injection site pruritus, injection site bruising) were observed in 23.9% of patients treated with BYDUREON BCISE.

Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions

Injection site reactions for BYDUREON BCISE-treated patients were more commonly observed in those with high titer anti-exenatide antibodies (?625) (27%) compared to those with low titer anti-exenatide antibodies (<625) (16%) or those who did not develop anti-exenatide antibodies (16%) [see Clinical Pharmacology (12.6)].

8 Use in Specific Populations

8.4 Pediatric Use

Additions and revisions underlined:

Use of BYDUREON BCISE for this indication is supported by a 24-week placebo-controlled trial with BYDUREON with 28-week open-label uncontrolled extension (Trial 9) in 82 pediatric patients 10 years of age and older with type 2 diabetes, a pediatric pharmacokinetic study, and studies in adults with type 2 diabetes mellitus [see Clinical Pharmacology (12.3) and Clinical Studies (14.2, 14.3, 14.4, 14.6)].

8.5 Geriatric Use

Additions and revisions underlined:

In two comparator-controlled 28-week trials, BYDUREON BCISE was studied in 74 patients (18%) who were at least 65 years of age and 10 (2.4%) patients who were at least 75 years of age. In these studies, no meaningful differences in safety and effectiveness were observed between patients ?65 years of age and younger adult patients, but these studies did not include sufficient numbers of patients ?75 years of age to determine whether they respond differently from younger adult patients.

In a large cardiovascular outcomes trial [see Clinical Studies (14.5)], BYDUREON was studied in 2,959 patients (40%) who were at least 65 years old and of those, 605 patients (8%) were at least 75 years old.

Use caution when initiating BYDUREON BCISE in geriatric patients because they are more likely to have decreased kidney function [see Use in Specific Populations (8.6)].

8.6 Renal Impairment

Additions and revisions underlined:

Pharmacokinetic studies of adult patients with renal impairment who received BYDUREON BCISE indicate that there is an increase in exenatide exposure in those with mild and moderate renal impairment as compared to patients with normal kidney function. BYDUREON BCISE may induce nausea and vomiting with transient hypovolemia and may worsen kidney function in patients with renal impairment.

Monitor patients with mild renal impairment for adverse reactions that may lead to hypovolemia. BYDUREON BCISE is not recommended for use in patients with eGFR below 45 mL/min/1.73 m2 or end-stage renal disease. If BYDUREON BCISE is used in patients with renal transplantation, closely monitor for adverse reactions that may lead to hypovolemia [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

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

Medication Guide

Additions and revisions underlined:

What are the possible side effects of BYDUREON BCISE? BYDUREON BCISE may cause serious side effects, including:

. . .

serious injection-site reactions. Serious injection-site reactions, with or without bumps (nodules), have happened in some people who use BYDUREON.

07/26/2022 (SUPPL-19)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Immunogenicity

Additions and/or revisions underlined

…

In the pediatric study [see Clinical Studies (14.3)], the maximum antibody titer obtained at any time during the study was low (<625) for approximately 29.3% of patients (17/58) and high (greater than or equal to 625) for approximately 63.8% of patients (37/58). The percentage of patients with positive antibody titers peaked at approximately Weeks 12 (60%, high titer) to 24 (54%, low titer) of dosing and then decreased to approximately 30.4% and 41.3%, respectively, by the end of the treatment period (Week 52). Patients with higher titers may have had an attenuated HbA1c response. At Week 24, the mean change in HbA1c in the treatment group was greater (-0.73%) in patients with low titer antibodies compared to +0.07% in patients with high titer antibodies.

…

06/10/2022 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Acute Gallbladder Disease

Additions and/or revisions underlined:

Acute events of gallbladder disease, such as cholelithiasis or cholecystitis, have been reported in GLP-1 receptor agonist trials and postmarketing. In the EXSCEL trial [see Clinical Studies (14.2)], 1.9% of BYDUREON-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

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Cholelithiasis and cholecystitis

In the EXSCEL trial [see Clinical Studies (14.2)], 1.9% of BYDUREON-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis.

…

6.3 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:

What are the possible side effects of BYDUREON BCISE?

…

gallbladder problems. Gallbladder problems have happened in some people who take BYDUREON. 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

…

07/22/2021 (SUPPL-17)

Approved Drug Label (PDF)

Boxed Warning

6.1 Clinical Trial Experience

Additions and/or revisions underlined:

… The data in this section are derived from pooled data from the controlled period of the 2 comparator- controlled trials in adults as well as data from the extension phase of one of these trials …

… Baseline estimated renal function was normal or mildly impaired (eGFRgreater than or equal to 60 mL/min/1.73 m2) in 93% of the pooled study populations.

The safety of BYDUREON, another formulation of exenatide extended-release, in pediatric patients age 10 to less than 18 years with type 2 diabetes was similar to that observed in the adults [see Clinical Studies (14.3)].

Common Adverse Reactions

Table 1 summarizes the adverse reactions with an incidence greater than or equal to 5% occurring in BYDUREON BCISE- treated adult patients in the pooled data …

Less Common Adverse Reactions

Adverse reactions that occurred in >2% and <5% of adult patients receiving BYDUREON BCISE during the controlled and extension phases …

Adverse Reactions Leading to Discontinuation of Therapy

The incidence of discontinuation of therapy due to adverse reactions was 3.9% for BYDUREON BCISE-treated patients in the two comparator-controlled 28-week trials in adults …

Other Adverse Reactions

Hypoglycemia

Table 2 summarizes the incidence of glucose level <54 mg/dL regardless of hypoglycemia clinical symptoms and the incidence of severe hypoglycemia in the two comparator-controlled 28-week trials of BYDUREON BCISE in adults.

Table 2: Incidence (% of Subjects) of Hypoglycemia (glucose <54 mg/dL) and Severe Hypoglycemia in Clinical Trials in Patients with Type 2 Diabetes Mellitus

Severe hypoglycemia was defined as clinical symptoms that were considered to result from hypoglycemia in which the patient required the assistance of another person and associated with recovery after oral carbohydrates, intravenous glucose or glucagon administration if no plasma glucose was available.

In the 24-week pediatric placebo-controlled clinical trial [see Clinical Studies (14.3)], 2 (3.4%) of BYDUREON-treated patients with type 2 diabetes had hypoglycemia with a blood glucose <54 mg/dL with or without symptoms and 1 (1.7%) had severe hypoglycemia (defined as an episode with severe cognitive impairment requiring external assistance for recovery.

Injection-Site Adverse Reactions

In the two comparator-controlled 28-week trials in adults, injection site reactions …

Increase in Heart Rate

In clinical trials of BYDUREON BCISE in adults, the mean increase from baseline in heart rate was 2.4 beats per minute.

6 Adverse Reactions

6.2 Immunogenicity

Additions and/or revisions underlined:

… Anti-exenatide antibodies were measured at prespecified intervals in the two comparator-controlled studies in adults, and evaluable anti-exenatide antibody measurements were available from 393 BYDUREON BCISE-treated patients …

… Evaluation of anti-exenatide antibodies in select adult patients with high-titer antibodies have demonstrated the potential for development of antibodies cross-reactive with endogenous GLP-1 and glucagon, but the clinical significance of these antibodies is not currently known …

… No information regarding the presence of neutralizing antibodies is currently available.

In the pediatric study [see Clinical Studies (14.3)], the maximum antibody titer obtained at any time during the study was low (<625) for approximately 30% of patients (17/57) and high (greater than or equal to 625) for approximately 63% of patients (36/57). The percentage of patients with positive antibody titers peaked at approximately Weeks 12 (58.8%, high titer) to 24 (55.1%, low titer) of dosing and then decreased to approximately 31% and 40%, respectively, by the end of the treatment period (Week 52). Patients with higher titers may have had an attenuated HbA1c response. At Week 24, the mean change in HbA1c in the treatment group was greater (-0.73%) in patients with low titer antibodies compared to +0.07% in patients with high titer antibodies.

The potential for development of antibodies cross-reactive with endogenous GLP-1 and glucagon has not been evaluated in pediatric patients. No information regarding the presence of neutralizing antibodies is currently available in pediatric patients.

6.3 Postmarketing Experience

Additions and/or revisions underlined:

Allergy/Hypersensitivity: injection-site reactions (e.g., abscess, cellulitis, and necrosis, with or without subcutaneous nodules), generalized pruritus and/or urticaria, macular or papular rash, angioedema; anaphylactic reaction.

7 Drug Interactions

Table 4: Clinically Relevant Interactions Affecting Drugs Co-Administered with BYDUREON BCISE and Other Exenatide-Containing Products

Concomitant Use of Insulin Secretagogues or Insulin

Intervention

Additions and/or revisions underlined:

When initiating BYDUREON BCISE, consider reducing the dose of concomitantly administered insulin secretagogue or insulin to reduce the risk of hypoglycemia.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of BYDUREON BCISE as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. Use of BYDUREON BCISE for this indication is supported by a 24-week placebo-controlled trial with BYDUREON with 28-week open-label uncontrolled extension in 82 pediatric patients aged 10 to less than 18 years with type 2 diabetes, a pediatric pharmacokinetic study, and studies in adults with type 2 diabetes mellitus [see Clinical Pharmacology (12.3) and Clinical Studies (14.1, 14.3)].

Safety and effectiveness of BYDUREON BCISE have not been established in pediatric patients less than 10 years of age.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What is BYDUREON?

BYDUREON BCISE is an injectable prescription medicine that may improve blood sugar (glucose) in adults and children who are 10 years of age and older with type 2 diabetes mellitus and should be used along with diet and exercise.

It is not known if BYDUREON is safe and effective for use in children younger than 10 years of age.

Do not use BYDUREON BCISE if:

you have had a severe allergic reaction to exenatide or any of the ingredients in BYDUREON BCISE. See the end of this Medication Guide for a complete list of ingredients in BYDUREON BCISE.

Symptoms of a severe allergic reaction with BYDUREON BCISE may include:

swelling of your face, lips, tongue, or throat
fainting or feeling dizzy
problems breathing or swallowing
very rapid heartbeat
severe rash or itching

Before using BYDUREON BCISE, tell your healthcare provider about all of your medical conditions, including if you:

Before using BYDUREON BCISE, talk to your healthcare provider about low blood sugar and how to manage it.

Especially tell your healthcare provider if you take:

other medicines to treat diabetes, including insulin or sulfonylureas.
a water pill (diuretic).
a blood pressure medicine.
warfarin.
a pain medicine.

How should I use BYDUREON BCISE?

Your healthcare provider should show you how to use BYDUREON BCISE before you use it for the first time.
Caregivers should help children with mixing and injecting BYDUREON BCISE.
BYDUREON BCISE is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm. Do not inject BYDUREON BCISE into a muscle (intramuscularly) or vein (intravenously).

What are the possible side effects of BYDUREON BCISE?

BYDUREON BCISE may cause serious side effects, including:

kidney problems. In people who have kidney problems, nausea, vomiting and diarrhea, may cause a loss of fluids (dehydration) which may cause kidney problems to get worse. These kidney problems include kidney failure. Dialysis or a kidney transplant may be needed.
- While taking BYDUREON BCISE: Call your healthcare provider right away if you have nausea, vomiting, or diarrhea that does not go away.
serious allergic reactions. Stop using BYDUREON and get medical help right away if you have any symptoms of a serious allergic reaction, including itching, rash, or difficulty breathing. See “Who should not use BYDUREON BCISE?

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Acute Pancreatitis

Inform patients treated with BYDUREON BCISE of the potential risk for pancreatitis …

Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

Inform patients that the risk of hypoglycemia is increased when BYDUREON 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)].

Instructions

Train patients on how to use BYDUREON BCISE properly prior to administration. Instruct patients and caregivers on proper mixing and injection technique to ensure the product is adequately mixed and a full dose is delivered. Instruct caregivers to assist pediatric patients with mixing and administration. Refer patients and caregivers to the accompanying Instructions for Use for complete administration instructions with illustrations [see Dosage and Administration (2)].

12/02/2020 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

(Additions and/or revisions underlined)

Patients receiving BYDUREON BCISE in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia [see Adverse Reactions (6.1) and Drug Interactions (7)].

The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) 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)

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

Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
Acute Pancreatitis [see Warnings and Precautions (5.2)]
Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3)]
Acute Kidney Injury [see Warnings and Precautions (5.4)]

6.2 Immunogenicity

(Additions and/or revisions underlined)

Anti-exenatide antibodies were measured at prespecified intervals in the two comparator-controlled studies., and evaluable anti-exenatide antibody measurements were available from 393 BYDUREON BCISE-treated patients. In these trials 40.2% of these patients developed low titer antibodies to exenatide and approximately 33.8% of patients developed high titer antibodies at any time during the studies. The percentage of patients with positive antibody titers peaked at approximately Weeks 8-16 of dosing and then diminished over time.

Change in HbA1c from baseline in patients with low titer antibodies at the last visit was generally comparable to that observed in antibody-negative patients at the last visit. However, patients with higher titer antibodies may have an attenuated HbA1c response.

Amongst BYDUREON BCISE-treated patients evaluable for antibodies (N=393), the incidence of potentially immunogenic injection site reactions (most commonly injection site nodule) during the 28-week studies was approximately 19.6%. These reactions were less commonly observed in antibody-negative patients (15.7%) and patients with low titer antibodies (16.3%) compared with those with high titer antibodies (27.2%).

Evaluation of anti-exenatide antibodies in select patients with high-titer antibodies have demonstrated the potential for development of antibodies cross-reactive with endogenous GLP-1 and glucagon, but the clinical significance of these antibodies is not currently known. In the BYDUREON BCISE clinical trials, 133 patients developed high titer antibodies to exenatide and 118 of these patients had samples and data for the cross-reactivity assay; one patient (0.8%) developed cross-reactive antibodies to GLP-1 and/or glucagon. No information regarding the presence of neutralizing antibodies is currently available.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

Inform patients that the risk of hypoglycemia is increased when BYDUREON BCISE 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)].

02/28/2020 (SUPPL-11)

Approved Drug Label (PDF)

4 Contraindications

Addition of the following bullet point underlined:

BYDUREON BCISE 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

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 BYDUREON BCISE immediately and do not re-expose the patient to exenatide. Upon discontinuation, thrombocytopenia can persist due to the prolonged exenatide exposure from BYDUREON BCISE (about 10 weeks) [see Adverse Reactions (6.3)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Drug-Induced Thrombocytopenia [see Warnings and Precautions (5.9)]
Acute Gallbladder Disease [see Warnings and Precautions (5.11)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following additional adverse reactions have been reported during post-approval use of BYDUREON BCISE or other formulations of exenatide. 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 (5.9)].

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

MEDICATION GUIDE

Additions and/or revisions underlined:

Do not use BYDUREON BCISE if:

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

What are the possible side effects of BYDUREON BCISE?

BYDUREON BCISE may cause serious side effects, including:

low blood platelet count (drug-induced thrombocytopenia). BYDUREON BCISE 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 BYDUREON BCISE and call your healthcare provider right away if you have unusual bleeding or bruising. Your blood platelet count may continue to be low for about 10 weeks after stopping BYDUREON BCISE.

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, e.g. bleeding, stop taking BYDUREON BCISE and seek medical advice promptly [see Warnings and Precautions (5.8)].

02/15/2019 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Acute Kidney Injury

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BYDUREON may induce nausea and vomiting with transient hypovolemia and may worsen renal function… Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including BYDUREON. BYDUREON is not recommended for use in patients with an eGFR below 45 mL/min/1.73 m2.

5.9 Acute Gallbladder Disease

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Acute events of gallbladder disease have been reported in GLP-1 receptor agonist trials. In the EXSCEL trial, 1.9% of BYDUREON-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.

8 Use in Specific Populations

8.5 Geriatric Use

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In five comparator-controlled 24- to 30-week trials, BYDUREON was studied in 132 patients (16.6%) who were at least 65 years old and 20 patients who were at least 75 years old. No differences in safety (N=152) and efficacy (N=52) were observed between these patients and the overall population, but the small sample size for patients ?75 years old limits conclusions. In a large cardiovascular outcomes trial, BYDUREON was studied in 2959 patients (40.3%) who were at least 65 years old and of those, 605 patients (8.2%) were at least 75 years old. Use caution when initiating BYDUREON in elderly patients because they are more likely to have decreased renal function.

8.6 Renal Impairment

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Pharmacokinetic studies of renally impaired patients receiving BYDUREON indicate that there is an increase in exposure in moderate and mild renally impaired patients as compared to patients with normal renal function. BYDUREON may induce nausea and vomiting with transient hypovolemia and may worsen renal function.

Monitor patients with mild renal impairment for adverse reactions that may lead to hypovolemia. BYDUREON is not recommended for use in patients with eGFR below 45 mL/min/1.73 m2 or end -stage renal disease. If used in patients with renal transplantation, closely monitor for adverse reactions that may lead to hypovolemia.

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

17 PATIENT COUNSELING INFORMATION

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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.