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Drug Safety-related Labeling Changes (SrLC)

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BYDUREON (NDA-022200)

(EXENATIDE SYNTHETIC)

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

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12/21/2022 (SUPPL-34)

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:

6.1 Clinical Trial Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.5 Geriatric Use

Additions and revisions underlined:

In five comparator-controlled 24- to 30-week trials, BYDUREON was studied in 132 patients (17%) who were between 65 years of age and 75 years of age and 20 (2.5%) patients who were at least 75 years of age. In these studies, no meaningful differences in safety (N=152) and effectiveness (N=52) 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 (14.4)], 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 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 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 may induce nausea and vomiting with transient hypovolemia and may worsen kidney function in patients with renal impairment.

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

Medication Guide

Additions and revisions underlined:

Pharmacokinetic studies of adult patients with renal impairment who received BYDUREON 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 may induce nausea and vomiting with transient hypovolemia and may worsen kidney function in patients with renal impairment.

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-32)

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-33)

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?

  • 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-31)

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 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 to bulleted lined listing underlined:

6.1 Clinical Trial Experience

Additions and/or revisions underlined:

… In an open-label 26-week trial, patients on metformin, a sulfonylurea, metformin plus a sulfonylurea, or metformin plus pioglitazone were treated with BYDUREON 2 mg every 7 days (weekly) or liraglutide 1.8 mg once daily.

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

Common Adverse Reactions

Tables 1 and 2 summarize adverse reactions in adults with an incidence greater than or equal to 5% reported in the six …

Adverse Reactions Leading to Study Withdrawal

The incidence of withdrawal due to adverse reactions in adults was 4.1% (N=57) for BYDUREON- treated patients …

Table 3 summarizes the incidence of hypoglycemia (defined as the presence of symptoms of hypoglycemia with a concomitant glucose <54 mg/dL and the ability to self-treat) in the six comparator- controlled 24- to 30-week trials in adults of BYDUREON used as monotherapy or as add-on to metformin, a sulfonylurea, a thiazolidinedione, or combination of these oral antidiabetic agents …

Table 3: Incidence (% of Subjects) of Hypoglycemia* in Clinical Trials in Patients with Type 2 Diabetes Mellitus

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 five comparator-controlled 24- to 30-week trials in adults, injection-site reactions were observed more frequently …

… Subcutaneous injection-site nodules may occur with the use of BYDUREON. In a separate 15-week study in adults in which information …

Increase in Heart Rate

Increases in heart rate from baseline ranging from 1.5 to 4.5 beats per minute have been observed in comparator-controlled clinical trials in adults.

Other Adverse Reactions

The following adverse reactions were also reported in three 30-week controlled trials in adults of BYETTA (N=963) add-on …

6.2 Immunogenicity

Additions and/or revisions underlined:

Anti-exenatide antibodies were measured at prespecified intervals (4-14 weeks) in all BYDUREON- treated adult patients (N=918) in five of the comparator-controlled studies of BYDUREON …

A total of 246 patients with antibodies to exenatide in the BYETTA and BYDUREON clinical trials were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. No treatment-emergent cross-reactive antibodies were observed across the range of titers.

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

… 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 and Other Exenatide-Containing Products

Concomitant Use of Insulin Secretagogues or Insulin

Intervention

Additions and/or revisions underlined:

When initiating BYDUREON, 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 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 for this indication is supported by a 24-week placebo-controlled trial 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)].

The safety and effectiveness of BYDUREON 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 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.

Who should not use BYDUREON?

Do not use BYDUREON if:

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

Symptoms of a severe allergic reaction with BYDUREON 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

What should I tell my healthcare provider before using BYDUREON?

Before using BYDUREON, 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?

  • Your healthcare provider should show you how to use BYDUREON before you use it for the first time.

  • Caregivers should help children with mixing and injecting BYDUREON.

  • BYDUREON is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm. Do not inject BYDUREON into a muscle (intramuscularly) or vein (intravenously).

What are the possible side effects of BYDUREON?

BYDUREON 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: 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?

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Acute Pancreatitis

Inform patients treated with BYDUREON 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 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)].

02/28/2020 (SUPPL-30)

Approved Drug Label (PDF)

4 Contraindications

Addition of the following bullet point underlined:

BYDUREON 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  (5.9)].

5 Warnings and Precautions

Newly added subsections:

5.2 Never Share a BYDUREON Pen Between Patients

BYDUREON pens must never be shared between patients. Pen-sharing poses a risk for transmission of blood-borne pathogens.

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

6 Adverse Reactions

Addition of the following to the bulleted line listing:

  • Never Share a BYDUREON Pen Between Patients [see Warnings and Precautions (5.2)]

  • Acute Pancreatitis [see Warnings and Precautions (5.3)]

  • 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 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:

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

BYDUREON may cause serious side effects, including:

  • Do not share your BYDUREON pen, prefilled syringe, or needles with another person. You may give another person an infection or get an infection from them.

Who should not use BYDUREON?

Do not use BYDUREON 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?

BYDUREON may cause serious side effects, including:

  • low blood platelet count (drug-induced thrombocytopenia). BYDUREON 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 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.

PATIENT COUNSELING INFORMATION

Newly added information:

Never Share a BYDUREON Pen Between Patients

Advise patients that they must never share a BYDUREON pen with another person, because doing so carries a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.2)].

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 and seek medical advice promptly [see Warnings and Precautions (5.9)].

02/15/2019 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Acute Kidney Injury

(Additions and/or revisions are underlined)

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 45mL/min/1.73m^2.

5.9 Acute Gallbladder Disease

(Additions and/or revisions are underlined)

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.

6 Adverse Reactions

6.1 Clinical Trial Experience

(Additions and/or revisions are underlined)

The safety data presented below are derived from six comparator-controlled trials of BYDUREON in patients who entered the studies not achieving adequate glycemic control on their current therapy.

6.2 Immunogenicity

(Additions and/or revisions are underlined)

…Of these patients, 50 (6% overall) had an attenuated glycemic response to BYDUREON (<0.7% reduction in HbA1c); the remaining 57 (6% overall) had a glycemic response comparable to that of patients without antibodies…

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions are underlined)

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

(Additions and/or revisions are underlined)

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

(Additions and/or revisions are 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.

10/20/2017 (SUPPL-25)

Approved Drug Label (PDF)

4 Contraindications

  • A prior serious hypersensitivity reaction to exenatide or to any of the product components. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with BYDUREON.

5 Warnings and Precautions

5.4 Acute Kidney Injury and Impairment of Renal Function

(Subsection title has been revised; Additions and/or revisions are underlined)

BYDUREON is not recommended for use 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…

5.6 Immunogenicity

(Additions and/or revisions are underlined)

Patients may develop antibodies to exenatide following treatment with BYDUREON. Anti-exenatide antibodies were measured in BYDUREON-treated patients in five of the six comparator-controlled 24- to 30-week studies of BYDUREON.

5.7 Hypersensitivity

(Additions and/or revisions are underlined)

…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 BYDUREON.

6 Adverse Reactions

(Additions and/or revisions are underlined)

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

Acute Kidney Injury and Impairment of Renal Function
6.1 Clinical Trial Experience

 (Additions and/or revisions are underlined)

The safety of BYDUREON was assessed in six comparator-controlled trials in patients who entered the studies not achieving adequate glycemic control on their current therapy… In an open-label 26-week trial, patients on metformin, a sulfonylurea, metformin plus a sulfonylurea, or metformin plus pioglitazone were treated with BYDUREON 2 mg every 7 days (weekly) or liraglutide 1.8 mg once daily.

 

Common Adverse Reactions

Tables 1 and 2 summarize adverse reactions with an incidence greater than or equal to 5% reported in the six comparator- controlled 24- to 30-week trials of BYDUREON used as monotherapy or as add-on to metformin, a sulfonylurea, a thiazolidinedione, or combination of these oral antidiabetic agents.

Table 1: Adverse Reactions Reported in Greater than or Equal to 5% of BYDUREON-Treated Patients with Type 2 Diabetes Mellitus in Monotherapy Trial

Table 2: Adverse Reactions Reported in Greater than or Equal to 5% of BYDUREON-Treated Patients with Type 2 Diabetes Mellitus in 24- to 30-Week Add-On Combination Therapy Trials

Nausea was a common adverse reaction associated with initiation of treatment with BYDUREON and usually decreased over time.

 

Adverse Reactions Leading to Study Withdrawal

The incidence of withdrawal due to adverse reactions was 4.1% (N=57) for BYDUREON-treated patients, 4.9% (N=13) for BYETTA-treated patients, and 2.9% (N=46) for other comparator-treated patients in the six comparator-controlled 24- to 30-week trials. The most common classes of adverse reactions (0.5%) leading to withdrawal for BYDUREON-treated patients were, Gastrointestinal Disorders 1.6% (N=22) versus 4.1% (N=11) for BYETTA and 1.9% (N=30) for other comparators, and Administration Site Conditions 0.8% (N=11) versus 0.0% for BYETTA and 0.2% (N=3) for other comparators. The most frequent adverse reactions within each of these respective classes were, nausea 0.4% (N=6) for BYDUREON versus 1.5% (N=4) for BYETTA and 0.8% (N=12) for other comparators, and injection-site nodule, 0.4% (N=6) for BYDUREON versus 0.0% for BYETTA and 0.0% for other comparators.

 

Hypoglycemia

Table 3 summarizes the incidence of minor hypoglycemia in the six comparator-controlled 24- to 30- week trials of BYDUREON used as monotherapy or as add-on to metformin, a sulfonylurea, a thiazolidinedione, or combination of these oral antidiabetic agents. In these trials, an event was classified as minor hypoglycemia if there were symptoms of hypoglycemia with a concomitant glucose <54 mg/dL and the patient was able to self-treat.

 

Table 3: Incidence (% of Subjects) of Minor† Hypoglycemia in Clinical Trials in Patients with Type 2 Diabetes Mellitus

 

Injection-Site Adverse Reactions

…The formation of subcutaneous nodules is consistent with the known properties of the microspheres used in BYDUREON.

 

Increase in Heart Rate

Increases in heart rate from baseline ranging from 1.5 to 4.5 beats per minute…

 

Other Adverse Reactions

The following adverse reactions were also reported in three 30-week controlled trials of BYETTA (N=963) add-on to metformin and/or sulfonylurea,…

6.2 Immunogenicity

(Additions and/or revisions are underlined)

…For these reasons, the incidence of antibodies to exenatide cannot be directly compared with the incidence of antibodies with other products.

6.3 Postmarketing Experience

(Additions and/or revisions are underlined)

The following additional adverse reactions have been reported during post-approval use of another formulation of exenatide…

7 Drug Interactions

(Additions and/or revisions are underlined)

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

(Table has been added; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

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

Risk Summary

Limited data with exenatide, the active ingredient in BYDUREON, in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy. Based on animal reproduction studies, there may be risks to the fetus from exposure to BYDUREON during pregnancy…

Animal reproduction studies identified increased adverse fetal and neonatal outcomes from exposure to exenatide extended-release during pregnancy, or from exposure to exenatide, during pregnancy and lactation, in association with maternal effects. In rats, exenatide extended-release administered during the period of organogenesis reduced fetal growth and produced skeletal ossification deficits at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 2 mg/week. In mice, exenatide administered during gestation and lactation caused increased neonatal deaths at doses that approximate clinical exposures at the MRHD. Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with an HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. 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

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

 

Data

Animal Data

Pregnant rats given subcutaneous doses of 0.3, 1, or 3 mg/kg exenatide extended-release every 3 days during organogenesis had systemic exposures 3-, 7-, and 17-times human exposure, respectively, at the maximum recommended human dose (MRHD) of 2 mg/week BYDUREON based on plasma exenatide exposure (AUC) comparison. Reduced fetal growth at all doses and skeletal ossification deficits at 1 and 3 mg/kg occurred at doses that decreased maternal food intake and body weight gain.

In studies evaluating reproduction and development in pregnant mice and rabbits, maternal animals were administered exenatide, the active ingredient in BYDUREON, by subcutaneous injection twice a day. Differences in embryo-fetal developmental toxicity from subcutaneously injected exenatide extended- release and exenatide were not evaluated in mice, rats, or rabbits.

In pregnant mice given 6, 68, 460, or 760 mcg/kg/day exenatide during fetal organogenesis, skeletal variations associated with slowed fetal growth, including changes in number of rib pairs or vertebral ossifications sites, and wavy ribs were observed at 760 mcg/kg/day, a dose that produced maternal toxicity and yielded systemic exposure 200 times the human exposure resulting from the MRHD of BYDUREON based on AUC comparison.

In pregnant rabbits given 0.2, 2, 22, 156, or 260 mcg/kg/day exenatide during fetal organogenesis, irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a dose yielding systemic exposure up to 4 times the human exposure from the MRHD of BYDUREON based on AUC comparison.

In maternal mice given 6, 68, or 760 mcg/kg/day exenatide from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths were observed on postpartum days 2 to 4 in dams given 6 mcg/kg/day, a dose yielding a systemic exposure equivalent to the human exposure from the MRHD of BYDUREON based on AUC comparison.

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 exenatide in human milk, the effects of exenatide on the breastfed infant, or the effects of exenatide on milk production. Exenatide, the active ingredient in BYDUREON, 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 exenatide and any potential adverse effects on the breastfed child from exenatide or from the underlying maternal condition.

 

Data

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

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

17 PATIENT COUNSELING INFORMATION

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

Risk of Hypoglycemia

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.

Risk of Acute Kidney Injury

Inform patients treated with BYDUREON of the potential risk for worsening kidney function…

Risk of Hypersensitivity Reactions

…Inform patients that if symptoms of hypersensitivity reactions occur, stop taking BYDUREON and seek medical advice promptly.

Instructions

…Inform patients formerly on BYETTA who start BYDUREON that they may experience transient elevations in blood glucose concentrations, which generally improve within the first 2 weeks after initiation of therapy

MEDICATION GUIDE

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What should I tell my healthcare provider before using BYDUREON?

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

  • are pregnant or plan to become pregnant. BYDUREON may harm your unborn baby. Tell your healthcare provider if you become pregnant while using BYDUREON. 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.

  • are breastfeeding or plan to breastfeed. It is not known if BYDUREON passes into your breast milk. You should talk with your healthcare provider about the best way to feed your baby while using BYDUREON.