2.1 Recommended Dosing

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The recommended dose of BYDUREON is 2 mg subcutaneously once every 7 days (weekly). The dose can be administered at any time of day, with or without meals.

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Discontinue an immediate- or extended-release exenatide product prior to initiation of BYDUREON. Patients changing from immediate-release exenatide to BYDUREON may experience transient (approximately 2 to 4 weeks) elevations in blood glucose concentrations.

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The day of weekly administration can be changed, if necessary, as long as the last dose was administered 3 or more days before the new day of administration.

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If a dose is missed, administer the dose as soon as noticed, provided the next regularly scheduled dose is due at least 3 days later. Thereafter, patients can resume their usual dosing schedule of once every 7 days (weekly).

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If a dose is missed and the next regularly scheduled dose is due 1 or 2 days later, do not administer the missed dose and instead resume BYDUREON with the next regularly scheduled dose.

2.2 Administration Instructions

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There are two presentations of BYDUREON (i.e., a single dose tray and a single dose pen). Each presentation of BYDUREON requires constitution prior to use to obtain a final concentration of 2 mg of exenatide per 0.65 mL of suspension.

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Prior to initiation, train patients and caregivers on proper mixing and injection [see Instruction for Use]. Instruct caregivers to assist pediatric patients with mixing and administration.

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Inspect BYDUREON visually before use. The suspension should appear white to off-white and cloudy. Do not use if particulate matter is present or if discoloration is observed.

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Immediately after the dose is prepared, administer BYDUREON subcutaneously to the abdomen, thigh, or upper arm region. Instruct patients to use a different injection site each week when injecting in the same region.

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When using BYDUREON with insulin, always administer BYDUREON and insulin as separate injections and never mix the products. It is acceptable to inject BYDUREON and insulin in the same body region but the injections should not be adjacent to each other.

5.1 Risk of Thyroid C-cell Tumors

In both genders of rats, exenatide extended-release caused a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures compared to controls [see Nonclinical Toxicology (13.1)]. A statistically significant increase in malignant thyroid C-cell carcinomas was observed in female rats receiving exenatide extended-release at 25-times clinical exposure compared to controls and higher incidences were noted in males above controls in all treated groups at ≥2-times clinical exposure. The potential of exenatide extended-release to induce C-cell tumors in mice has not been evaluated. Other GLP-1 receptor agonists have also induced thyroid C-cell adenomas and carcinomas in male and female mice and rats at clinically relevant exposures. It is unknown whether BYDUREON will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of exenatide extended-release-induced rodent thyroid C-cell tumors has not been determined.

Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.

BYDUREON is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk of MTC with the use of BYDUREON and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).

Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with BYDUREON. Such monitoring may increase the risk of unnecessary procedures, due to the low specificity of serum calcitonin testing for MTC and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.

5.2 Acute Pancreatitis

Based on postmarketing data, exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYDUREON, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, BYDUREON should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, BYDUREON should not be restarted. Consider antidiabetic therapies other than BYDUREON in patients with a history of pancreatitis.

5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

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.

5.4 Acute Kidney Injury

BYDUREON may induce nausea and vomiting with transient hypovolemia and may worsen renal function. There have been postmarketing reports of altered renal function with exenatide, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring hemodialysis or kidney transplantation. Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or hydration status such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or diuretics. Some events occurred in patients who had been experiencing nausea, vomiting or diarrhea, with or without dehydration. 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 [see Use in Specific Populations (8.6)].

5.5 Gastrointestinal Disease

Exenatide has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Because exenatide is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea, the use of BYDUREON is not recommended in patients with severe gastrointestinal disease.

5.6 Immunogenicity

In the 24- to 30-week treatment periods in Trials 1, 2, 3, 4 and 9 in adult patients with type 2 diabetes mellitus [see Clinical Studies (14.2, 14.3) and Adverse Reactions (6.1)], BYDUREON-treated patients who had high titer anti-exenatide antibodies (defined as ≥625) had a lower glycemic response compared to BYDUREON-treated patients who did not have anti-exenatide antibodies [see Clinical Pharmacology (12.6)].

In the 24-week treatment period in Trial 8 in pediatric patients with type 2 diabetes mellitus [see Clinical Studies (14.5)], BYDUREON-treated patients who had high titer anti-exenatide antibodies (≥625) appeared to have had a lower glycemic response compared to BYDUREON-treated patients who did not have anti exenatide antibodies. At Week 24, the mean change in HbA1c from baseline in BYDUREON-treated patients was greater (-0.73%) in those with low titer anti-exenatide antibodies (<625) compared to +0.07% in those with high titer anti-exenatide antibodies [see Clinical Pharmacology (12.6)].

If there is worsening glycemic control or failure to achieve targeted glycemic control, consider stopping BYDUREON and using alternative antidiabetic therapy.

5.7 Hypersensitivity

There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) in patients treated with exenatide. If a hypersensitivity reaction occurs, the patient should discontinue BYDUREON and promptly seek medical advice [see Contraindications (4) and Adverse Reactions (6.3)]. 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.

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 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)].

5.9 Injection-Site Reactions

There have been postmarketing reports of serious injection-site reactions (e.g., abscess, cellulitis, and necrosis), with or without subcutaneous nodules, with the use of BYDUREON. Isolated cases required surgical intervention [see Adverse Reactions (6.1)].

5.10 Acute Gallbladder Disease

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.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data presented below are derived from six comparator-controlled trials of BYDUREON in adult patients who entered the studies not achieving adequate glycemic control on their current therapy [see Clinical Studies (14.1)]. In a double-blind 26-week trial, patients on diet and exercise were treated with BYDUREON 2 mg once every 7 days (weekly), sitagliptin 100 mg daily, pioglitazone 45 mg daily, or metformin 2000 mg daily. In a double-blind 26-week trial, patients on metformin were treated with BYDUREON 2 mg once every 7 days (weekly), sitagliptin 100 mg daily, or pioglitazone 45 mg daily. In an open-label 26-week trial, patients on metformin or metformin plus sulfonylurea were treated with BYDUREON 2 mg once every 7 days (weekly) or optimized insulin glargine. In two open-label 24- to 30-week studies, patients on diet and exercise or metformin, a sulfonylurea, a thiazolidinedione, or combination of oral agents were treated with BYDUREON 2 mg once every 7 days (weekly) or BYETTA 10 mcg twice daily. 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 ≥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 ≥5% of BYDUREON-Treated Patients with Type 2 Diabetes Mellitus in Monotherapy Trial

Table 2: Adverse Reactions Reported in ≥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 in adults 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 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.

In the 24-week pediatric placebo-controlled clinical trial (Trial 8) [see Clinical Studies (14.5)], 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 Including Nodules

In five comparator-controlled 24- to 30-week trials in adults, injection-site reactions were observed more frequently in BYDUREON-treated patients (17%) than in BYETTA-treated patients (13%), titrated insulin glargine-treated patients (1.8%), or placebo-treated patients (sitagliptin (11%), pioglitazone (6%), and metformin (13%) treatment groups). One percent of BYDUREON-treated patients withdrew due to injection-site adverse reactions (injection-site mass, injection-site nodule, injection-site pruritus, and injection-site reaction).

In a separate 15-week study of BYDUREON in adults in which information on nodules were collected and analyzed, 24 out of 31 subjects (77%) experienced at least 1 injection-site nodule during treatment; 2 subjects (7%) reported accompanying localized symptoms. The mean duration of events was 27 days.

Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions

Injection site reactions for BYDUREON-treated patients were more commonly observed in those who were antibody-positive (anti-exenatide antibodies) (14%) compared with those who were antibody-negative (3%) [see Clinical Pharmacology (12.6)].

Increase in Heart Rate

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

Cholelithiasis and cholecystitis

In the EXSCEL trial [see Clinical Studies (14.4)], 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.

Other Adverse Reactions

The following adverse reactions were also reported in three 30-week controlled trials (in adults with type 2 diabetes mellitus) of BYETTA (N=963) add-on to metformin and/or sulfonylurea, with an incidence of ≥1% and reported more frequently than with placebo: feeling jittery (9% BYETTA, 4% placebo), dizziness (9% BYETTA, 6% placebo), asthenia (4% BYETTA, 2% placebo), and hyperhidrosis (3% BYETTA, 1% placebo).

6.2 Postmarketing Experience

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.

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.

Blood and Lymphatic Systems: drug induced thrombocytopenia.

Drug Interactions: increased international normalized ratio (INR), sometimes associated with bleeding, with concomitant warfarin use [see Drug Interactions (7)].

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)].

Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy.

Neurologic: dysgeusia; somnolence.

Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant and kidney transplant dysfunction.

Skin and Subcutaneous Tissue Disorders: alopecia.

8.1 Pregnancy

8.2 Lactation

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 (see Data).

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.

8.4 Pediatric Use

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 (Trial 8) 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, 14.5)].

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

8.5 Geriatric Use

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

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.

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 BYDUREON 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)].

12.1 Mechanism of Action

Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. BYDUREON is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.

The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide is a GLP-1 receptor agonist that has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide promotes insulin release from pancreatic beta-cells in the presence of elevated glucose concentrations.

12.2 Pharmacodynamics

Exenatide improves glycemic control through the actions described below.

12.3 Pharmacokinetics

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of BYDUREON or of other exenatide products.

Immunogenicity in Adult Patients

Anti-exenatide antibodies were measured at prespecified intervals (4-14 weeks) in BYDUREON-treated adult patients (N=918) in five active-controlled trials for the improvement of glycemic control in adults with type 2 diabetes mellitus (Trials 1, 2, 3, 4 and 9) [see Clinical Studies (14.2, 14.3) and Adverse Reactions (6.1)]. In these five trials, 107/918 (12%) of BYDUREON-treated patients had high titer anti-exenatide antibodies (high titer was defined as ≥625) at endpoint. These patients had a lower glycemic response compared to BYDUREON-treated patients who did not have anti-exenatide antibodies at endpoint [see Warnings and Precautions (5.6)].

In a 30-week, randomized, open-label, controlled trial in adults with type 2 diabetes mellitus [see Adverse Reactions (6.1)], anti-exenatide antibody assessments were performed at baseline and at 4-week intervals from Week 6 to Week 30. The mean anti-exenatide antibody titer in the BYDUREON-treated patients peaked at Week 6.

Injection site reactions for BYDUREON-treated patients were more commonly observed in those who were antibody-positive (anti-exenatide antibodies) compared with those who were antibody-negative, with a greater incidence in those with higher titer anti-exenatide antibodies (defined as ≥625) [see Adverse Reactions (6.1)]. There is insufficient data to assess whether the observed anti-exenatide antibodies in adults had an effect on the severity of injection site reactions, or on the incidence or severity of hypersensitivity reactions.

A total of 32 adult patients with anti-exenatide antibodies in BYDUREON Trial 9 were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon and no treatment-emergent cross-reactive antibodies were observed.

Immunogenicity in Pediatric Patients

In a 52-week trial (24-week controlled and 28-week extended treatment period) for the improvement of glycemic control in pediatric patients with type 2 diabetes mellitus (Trial 8) [see Clinical Studies (14.5)], 37/58 (64%) of BYDUREON-treated patients had high titer anti-exenatide antibodies (high titer was defined as ≥625) at any time during the study. In this trial, 60% of these patients had a peak high-titers at approximately Week 12. BYDUREON-treated pediatric patients that had high titer anti-exenatide antibodies appeared to have had a lower glycemic response compared to BYDUREON-treated pediatric patients who did not have anti-exenatide antibodies during this trial [see Warnings and Precautions (5.6)].

There is insufficient data to assess whether the observed anti-exenatide antibodies in pediatric patients had an effect on the incidence or severity of hypersensitivity reactions or injection site reactions.

The potential for development of antibodies cross-reactive with endogenous GLP-1 and glucagon has not been evaluated in BYDUREON-treated pediatric patients.

Anti-Drug Antibody Effects on Pharmacokinetics in Adult and Pediatric Patients

The percentage of exenatide-treated adult and pediatric patients (age ≥11 years) with high anti-exenatide antibody titers (≥625) that had steady state exenatide plasma concentrations below limit of quantitation was higher than in those with low anti exenatide antibody titers (<625).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Thyroid C-cell tumors have been observed in rats and mice with GLP-1 receptor agonists.

A 2‑year carcinogenicity study was conducted with exenatide extended-release, the active component of BYDUREON, in male and female rats at doses of 0.3, 1.0, and 3.0 mg/kg (2-, 9-, and 26-times human systemic exposure at the maximum recommended human dose (MRHD) of 2 mg/week BYDUREON based on plasma exenatide AUC, respectively) administered by subcutaneous injection every other week. In this study there was an increased incidence of C-cell adenomas and C-cell carcinomas at all doses. An increase in benign fibromas was seen in the skin subcutis at injection sites of males given 3 mg/kg. No treatment-related injection-site fibrosarcomas were observed at any dose. The human relevance of these findings is currently unknown.

Carcinogenicity of exenatide extended-release has not been evaluated in mice.

Exenatide, the active ingredient in BYDUREON, was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay.

In mouse fertility studies with exenatide, the active ingredient in BYDUREON, at twice-daily subcutaneous doses of 6, 68, or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating, and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 148 times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC.

14.1 Overview of Clinical Trials

BYDUREON has been studied in adult patients with type 2 diabetes mellitus as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, a combination of metformin and a thiazolidinedione, in combination with a SGLT2 inhibitor on a background of metformin, and in combination with basal insulin [see Clinical Studies (14.2, 14.3)].

Cardiovascular (CV) outcomes were studied in the EXSCEL trial that enrolled adult patients with type 2 diabetes mellitus and multiple risk factors for CV disease or established CV disease [see Clinical Studies (14.4)].

BYDUREON has been studied in pediatric patients aged 10 years and older with type 2 diabetes mellitus as monotherapy and in combination with metformin, a sulfonylurea, and in combination with basal insulin with or without metformin [see Clinical Studies (14.5)].

14.2 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus - Monotherapy

BYDUREON Monotherapy versus Metformin, Sitagliptin, and Pioglitazone

A 26-week, randomized, comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to metformin, sitagliptin, and pioglitazone in adult patients with type 2 diabetes whose glycemic control was inadequate with diet and exercise (Trial 1 - NCT00676338). Patients were randomly assigned to receive BYDUREON 2 mg given subcutaneously once every seven days (weekly), titrated metformin from 1000 to 2500 mg/day, sitagliptin 100 mg/day or titrated pioglitazone from 30 to 45 mg/day, all dosed according to approved labeling.

A total of 820 patients were studied: 552 (67%) were Caucasian, 102 (12%) were East Asian, 71 (9%) were West Asian, 65 (8%) were Hispanic, 25 (3.0%) were Black, 4 (0.5%) were Native American, and 1 was classified otherwise. The mean baseline HbA1c was 8.5%.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation).

Efficacy Results:

Treatment with BYDUREON 2 mg once weekly (QW) resulted in mean HbA1c reduction that was statistically significantly greater compared to sitagliptin 100 mg/day. The mean reduction in HbA1c was non-inferior compared with metformin 1000-2500 mg/day (mean dose 2077 mg/day at study endpoint). Non-inferiority of BYDUREON 2 mg QW to pioglitazone 30 45 mg/day (mean dose 40 mg/day at study endpoint) in reducing HbA1c after 26 weeks of treatment was not demonstrated (the mean change from baseline in HbA1c after 26 weeks was -1.6% with BYDUREON and -1.7% with pioglitazone). The non-inferiority margin was set at +0.3% in this study. The results for the primary endpoint at 26 weeks are summarized in Table 5.

The proportion of patients with a Week 26 value achieving HbA1c of less than 7% at Week 26 were 56%, 52%, 40%, and 55% for BYDUREON, metformin, sitagliptin, and pioglitazone, respectively. Patients who did achieve HbA1c goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose were -41 mg/dL, -36 mg/dL, -20 mg/dL, and -46 mg/dL, and for body weight were -2.0 kg, -2.0 kg, -0.8 kg, and +1.5 kg for BYDUREON, metformin, sitagliptin, and pioglitazone, respectively.

14.3 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus - Combination Therapy

BYDUREON versus Sitagliptin and Pioglitazone, All as Add-on to Metformin Therapy

A 26-week double-blind comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to sitagliptin and pioglitazone in patients with type 2 diabetes whose glycemic control was inadequate with metformin therapy (Trial 2 - NCT00637273). Patients were randomly assigned to receive BYDUREON 2 mg given subcutaneously once every 7 days (weekly), sitagliptin 100 mg/day or pioglitazone 45 mg/day, in addition to their existing metformin therapy.

A total of 491 patients were studied 168 (34.2%) were Caucasian, 143 (29.1%) were Hispanic, 119 (24.2%) were Asian, 52 (10.6%) were Black, 3 (0.6%) were Native American, and 6 (1.2%) were classified otherwise. The mean baseline HbA1c was 8.5%.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation).

Efficacy Results:

In this study, treatment with BYDUREON 2 mg QW resulted in a statistically significant mean HbA1c reduction compared to sitagliptin 100 mg/day. There was a numerically greater reduction in HbA1c with BYDUREON compared to pioglitazone, but there was not sufficient evidence to conclude superiority of BYDUREON 2 mg QW to pioglitazone 45 mg/day in reducing HbA1c after 26 weeks of treatment. Results for the primary endpoint at 26 weeks are summarized in Table 6.

The proportion of patients with a Week 26 value achieving HbA1c of less than 7% at Week 26 were 46%, 30%, and 39% for BYDUREON, sitagliptin, and pioglitazone, respectively. Patients who did achieve an HbA1c goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose were -32 mg/dL, -16 mg/dL and -27 mg/dL, and for body weight were -2.3 kg, -0.8 kg and +2.8 kg for BYDUREON, sitagliptin, and pioglitazone, respectively.

BYDUREON versus Insulin Glargine, Both as Add-on to Metformin or Metformin + Sulfonylurea Therapy

A 26-week open-label comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to titrated insulin glargine in patients with type 2 diabetes whose glycemic control was inadequate with metformin or metformin plus sulfonylurea therapy (Trial 3 - NCT00641056). Patients were randomly assigned to receive BYDUREON 2 mg given subcutaneously once every 7 days (weekly) or insulin glargine once daily in addition to their existing oral antidiabetic therapy. Insulin glargine was dosed to a target fasting glucose concentration of 72 to 100 mg/dL.

The mean dose of insulin glargine was 10 units/day at baseline and 31 units/day at endpoint. At Week 26, 21% of insulin glargine treated patients were at fasting glucose goal.

A total of 456 patients were studied: 379 (83.1%) were Caucasian, 47 (10.3%) were Hispanic, 25 (5.5%) were East Asian, 3 (0.7%) were Black, and 2 (0.4%) were West Asian. Background therapy was either metformin (70%) or metformin plus sulfonylurea (30%). The mean baseline HbA1c was 8.3%.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation).

Efficacy Results:

Treatment with BYDUREON once weekly resulted in a mean reduction in HbA1c from baseline at 26 weeks of -1.5%. The mean reduction in HbA1c seen in insulin glargine arm at 26 weeks was -1.3%. The difference in observed effect size between BYDUREON and glargine in this trial excluded the pre-specified non-inferiority margin of +0.3%.

The proportion of patients with a Week 26 value achieving HbA1c of less than 7% at Week 26 were 57% and 48% for BYDUREON and insulin glargine, respectively. Patients who did achieve an HbA1c goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose in this study were -38 mg/dL and -50 mg/dL, and for body weight were -2.6 kg and +1.4 kg for BYDUREON and insulin glargine, respectively.

BYDUREON versus BYETTA, Both as Monotherapy or as Add-on to Metformin, a Sulfonylurea, a Thiazolidinedione, or Combination of Oral Agents

A 24-week, randomized, open-label trial was conducted to compare the safety and efficacy of BYDUREON to BYETTA in patients with type 2 diabetes and inadequate glycemic control with diet and exercise alone or with oral antidiabetic therapy, including metformin, a sulfonylurea, a thiazolidinedione, or combination of two of those therapies (Trial 4 - NCT00877890). Patients were randomly assigned to receive BYDUREON 2 mg subcutaneously once every 7 days (weekly) or BYETTA (10 mcg subcutaneously twice daily), in addition to existing oral antidiabetic agents. Patients assigned to BYETTA initiated treatment with 5 mcg twice daily then increased the dose to 10 mcg twice daily after 4 weeks.

A total of 252 patients were studied: 149 (59%) were Caucasian, 78 (31%) Hispanic, 15 (6%) Black, and 10 (4%) Asian. Patients were treated with diet and exercise alone (19%), a single oral antidiabetic agent (47%), or combination therapy of oral antidiabetic agents (35%). The mean baseline HbA1c was 8.4%.

The primary endpoint was change in HbA1c from baseline to Week 24 (or the last value at time of early discontinuation).

Efficacy Results:

Treatment with BYDUREON 2 mg QW resulted in a statistically significantly greater mean HbA1c reduction compared to BYETTA 10 mcg twice daily. Change in body weight was a secondary endpoint. Twenty-four-week study results are summarized in Table 7.

Reductions from mean baseline (97/94 kg) in body weight were observed in both BYDUREON (−2.3 kg) and BYETTA (−1.4 kg) treatment groups.

BYDUREON versus Liraglutide, Both as Add-on to Metformin, a Sulfonylurea, Metformin + Sulfonylurea, or Metformin + Pioglitazone Therapy

A 26-week open-label comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to liraglutide in patients with type 2 diabetes whose glycemic control was inadequate with metformin, a sulfonylurea, metformin plus sulfonylurea, or metformin plus pioglitazone therapy (Trial 5 - NCT01029886). Patients were randomly assigned to receive BYDUREON 2 mg given subcutaneously once every 7 days (weekly) or liraglutide uptitrated from 0.6 mg/day to 1.2 mg/day, then 1.8 mg/day in addition to their existing oral antidiabetic therapy. Each titration was to be completed after at least one week, but could be delayed if the patient had severe nausea or vomiting as established by the investigator. Patients not tolerating the 1.8 mg/day dose of liraglutide by Week 4 were discontinued from the study.

A total of 911 patients were studied: 753 (82.7%) were Caucasian, 111 (12.2%) were Asian, 32 (3.5%) were American Indian or Alaska Native, 8 (0.9%) were Black, 6 (0.7%) were multiple races, and 1 (0.1%) was Pacific Islander. Background therapy was either a single oral antidiabetic agent (35%) or a combination of oral antidiabetic agents (65%). The mean baseline HbA1c was 8.4%.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation).

Efficacy Results:

Treatment with BYDUREON once weekly resulted in a mean reduction in HbA1c from baseline at 26 weeks of -1.3%. The mean reduction in HbA1c seen in the liraglutide arm at 26 weeks was -1.5%. The HbA1c reduction with BYDUREON did not meet predefined non-inferiority criteria compared to liraglutide 1.8 mg/day. The non-inferiority margin was set at +0.25% in this study. Results for the primary endpoint at 26 weeks are summarized in Table 8.

The proportion of patients with a Week 26 value achieving HbA1c of less than 7% at Week 26 were 48% and 56% for BYDUREON and liraglutide, respectively. Patients who did achieve an HbA1c goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose were -32 mg/dL and -38 mg/dL, and for body weight were -2.7 kg and -3.6 kg for BYDUREON and liraglutide, respectively.

14.4 EXSCEL Cardiovascular Outcomes Trial in Adult Patients with Type 2 Diabetes Mellitus

EXSCEL was a multinational, placebo-controlled, double-blind, randomized, parallel group pragmatic study that evaluated cardiovascular (CV) outcomes during treatment with BYDUREON in adult patients with type 2 diabetes and any level of CV risk when added to the current usual care (NCT01144338). A total of 14,752 adult patients were randomized 1:1 to either BYDUREON 2 mg given subcutaneously once weekly or placebo and followed as in routine clinical practice for a median of 38.7 months with a median treatment duration of 27.8 months.

Ninety six percent of the patients in both treatment groups completed the study in accordance with the protocol, and the vital status was known at the end of the study for 98.9% and 98.8% of the patients in the BYDUREON and placebo group, respectively. The mean age at study entry was 62 years (21 to 92 years with 8.5% of the patients ≥75 years). Approximately 62.0% of the patients were male, 75.8% were Caucasian, 9.8% were Asian, 6.0% were Black, and 20.5% were Hispanic or Latino. The mean BMI was 32.7 kg/m2 and the mean duration of diabetes was 13.1 years. Approximately 49.3% had mild renal impairment (estimated glomerular filtration rate [eGFR] ≥60 to ≤89 mL/min/1.73 m2) and 21.6% had moderate renal impairment (eGFR ≥30 to ≤59 mL/min/1.73 m2).

The mean HbA1c was 8.1%. At baseline, 1.5% of patients were not treated with either oral antidiabetic medications or insulin, 42.3% were treated with one oral antidiabetic medication and 42.4% were treated with two or more oral antidiabetic medications. Usage of oral antidiabetic medications included metformin (76.6%), sulfonylurea (36.6%), DPP-4 inhibitors (14.9%), thiazolidinediones (3.9%), and SGLT2 inhibitors (0.9%). Overall insulin usage was 46.3% (13.8% with insulin alone and 32.6% with insulin and one or more oral antidiabetic medications).

Overall, at baseline, 26.9% of patients did not have established cardiovascular (CV) disease, while 73.1% had established CV disease. The concomitant use of CV medications (e.g., ACE inhibitors, angiotensin receptor blockers, diuretics, beta blockers, calcium channel blockers, antithrombotic and anticoagulants, and lipid-lowering agents) was similar in the BYDUREON and placebo groups. At baseline, the mean systolic blood pressure was 135.5 mmHg, the mean diastolic blood pressure was 78.1 mmHg, the mean LDL was 95.0 mg/dL, and the mean HDL was 44.0 mg/dL.

The primary endpoint in EXSCEL was the time to first confirmed Major Adverse Cardiac Event (MACE) from randomization. MACE was defined as occurrence of either a cardiovascular (CV)-related death, or a nonfatal myocardial infarction (MI) or a nonfatal stroke. All-cause mortality, CV-related death, and fatal or nonfatal MI or stroke, hospitalization for acute coronary syndrome, and hospitalization for heart failure were also assessed as secondary endpoints.

A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated. Type-1 error was controlled across multiple tests using a hierarchical testing strategy.

MACE Results:

BYDUREON did not increase the risk of MACE in adult patients with type 2 diabetes mellitus (HR: 0.91; 95% CI: 0.832, 1.004; P<0.001 for non-inferiority; P=0.06 for superiority). See results in Table 10 and Figure 2. The incidence of MACE in patients with and without established CV disease was 13.4% in the BYDUREON group versus 14.6% in the placebo group and 6.0% (BYDUREON) versus 5.9% (placebo), respectively. Five hundred and seven (507) patients (6.9%) died in the BYDUREON group versus 584 (7.9%) in the placebo group.

Figure 2: Time to First Adjudicated MACE in Adult Patients with Type 2 Diabetes (EXSCEL)

HR=hazard ratio, CI=confidence interval.

14.5 Glycemic Control Trial in Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus

The efficacy and safety of BYDUREON 2 mg given subcutaneously once weekly or placebo was evaluated in a 24 week randomized, double blind, placebo controlled, parallel group study (Trial 8 - NCT01554618) in 82 patients aged 10 to 17 years with type 2 diabetes treated with diet and exercise alone or in combination with a stable dose of oral antidiabetic agents and/or insulin. This study included a 28-week open-label long-term extension in which patients in both treatment groups received BYDUREON 2 mg given subcutaneously once weekly after the 24-week controlled period.

In this trial, 88% of patients completed the assessment period. The mean age at study entry was 15.1 years (13% were 11 to 12 years old, 59% were 13 to 16 years old and 28% were older than 16 years). Approximately 42% of the patients were male, 43% were White, 4% were Asian, 31% were Black or African American, 6% were American Indian or Alaska Native, and 44% were Hispanic or Latino. The mean body weight was 100.6 kg (67% were in ≥97 weight percentile group, 26% in ≥85 to <97 and 6% in ≥3 to <85), mean BMI was 36.4 kg/m2 and the mean duration of diabetes was 2.3 years.

At baseline, mean HbA1c was 8.17%, 12.2% of patients were not treated with either oral antidiabetic medications or insulin, 40.2% were treated with one oral antidiabetic medication and 1.2% were treated with two oral antidiabetic medications. 79.3% of patients were receiving metformin and 1.2% were receiving sulfonylurea. Overall insulin usage was 46.3% (8.5% with insulin alone and 37.8% with insulin and one other oral antidiabetic medication).

The primary endpoint of the study was the change in HbA1c from baseline to Week 24.

Efficacy Results:

BYDUREON was superior to placebo in reducing HbA1c (Table 11).

The mean changes from baseline to Week 24 for body weight were -0.17 kg with (SE 0.7) and +0.88 kg (SE 1.0) for BYDUREON and placebo, respectively.

Table 11: Results of 24-Week Trial of BYDUREON versus Placebo, Both alone or in Combination with Oral Antidiabetic Agents and/or Insulin in Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus