Exenatide

BYDUREON BCISE (exenatide) extended-release injectable suspension is a GLP-1 receptor agonist supplied as a sterile suspension of exenatide extended-release microspheres in an oil-based vehicle of medium chain triglycerides (MCT), in a single-dose autoinjector. Redispersion by mixing provides a white to off-white, opaque, suspension to be administered by subcutaneous injection. Each autoinjector contains sufficient suspension to deliver 2 mg of exenatide extended-release in a volume of 0.85 mL. Exenatide is a 39-amino acid synthetic peptide amide with an empirical formula of C 184 H 282 N 50 O 60 S and a molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below. H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 Exenatide is incorporated in an extended-release microsphere formulation containing the 50:50 poly (D,L-lactide-co-glycolide) polymer (37.2 mg per dose) along with sucrose (0.8 mg per dose), suspended in the vehicle, MCT (774.4 mg per dose).

BYDUREON BCISE is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Limitations of Use • BYDUREON BCISE contains exenatide. Coadministration with other exenatide-containing products is not recommended. BYDUREON BCISE is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. ( 1 ) Limitations of Use: • Coadministration with other exenatide containing products is not recommended. ( 1 )

How Supplied • BYDUREON BCISE contains 2 mg of exenatide in 0.85 mL vehicle, in a pre-filled, single-dose autoinjector. Redispersion by mixing provides a white to off-white, opaque, extended-release injectable suspension, available in cartons that contain four single-dose autoinjectors (NDC 0310-6540-04). Storage and Handling • BYDUREON BCISE must be stored FLAT. • Store the autoinjector in the original package. Protect from light. Do not use past the expiration date. • Store BYDUREON BCISE in the refrigerator at 36°F to 46°F (2°C to 8°C). • BYDUREON BCISE can be kept at room temperature not to exceed 86°F (30°C) for no more than a total of 4 weeks, if needed. • Discard BYDUREON BCISE after use in a puncture-resistant container.

• Administer 2 mg by subcutaneous injection once every seven days (weekly), at any time of day and with or without meals. (2.1) • Administer immediately after the dose is prepared. See full prescribing information for additional administration instructions. (2.2) 2.1 Recommended Dosage • The recommended dosage of BYDUREON BCISE is 2 mg subcutaneously once every 7 days (weekly). The dose can be administered at any time of day, with or without meals. • Discontinue an immediate- or extended-release exenatide product prior to initiation of BYDUREON BCISE. Patients changing from another extended-release exenatide product to BYDUREON BCISE may do so at the next regularly scheduled dose. Patients changing from immediate-release exenatide to BYDUREON BCISE may experience transient (approximately 2 to 4 weeks) elevations in blood glucose concentrations. • 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. Recommendations Regarding Missed Dose • 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, administer subsequent doses once every 7 days (weekly). • 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 BCISE with the next regularly scheduled dose. 2.2 Administration Instructions • Prior to initiation, train patients and caregivers on proper mixing and injection [see Instructions for Use ] . Instruct caregivers to assist pediatric patients with mixing and administration. • Remove the autoinjector from the refrigerator 15 minutes prior to mixing the injection, in order to reach room temperature. • Mix by shaking vigorously for at least 15 seconds. • Inspect BYDUREON BCISE visually before use. After mixing, BYDUREON BCISE should appear as an opaque, cloudy, white to off-white suspension, evenly mixed with no residual medicine along the side, bottom or top of the inspection window. Do not use if particulate matter is present or if discoloration is observed. • Administer BYDUREON BCISE immediately after the autoinjector is prepared as a subcutaneous injection in the abdomen, thigh, or upper arm region. Advise patients to use a different injection site each week when injecting in the same region. • When using BYDUREON BCISE with insulin, instruct patients to administer as separate injections and to never mix the products. It is acceptable to inject BYDUREON BCISE and insulin in the same body region, but the injections should not be adjacent to each other.

BYDUREON BCISE is contraindicated in patients with a: • Personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). • Prior serious hypersensitivity reaction to exenatide or to any of the excipients of BYDUREON BCISE. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with exenatide [see Warnings and Precautions (5.7) ] . • 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) ] . • Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2. (4) • Prior serious hypersensitivity reaction to exenatide or any of the product components. (4) • History of drug-induced immune-mediated thrombocytopenia from exenatide products. ( 4 )

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Thyroid C-cell Tumors Inform patients that exenatide extended-release causes benign and malignant thyroid C-cell tumors in rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia, or dyspnea) to their physician [see Boxed Warning and Warnings and Precautions (5.1) ] . Acute Pancreatitis Inform patients of the potential risk for acute pancreatitis and its symptoms: severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting. Instruct patients to discontinue BYDUREON BCISE promptly and contact their physician if pancreatitis is suspected [see Warnings and Precautions (5.2) ] . 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) ] . 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) ] . Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of exenatide. Inform patients that if symptoms of hypersensitivity reaction occur, stop taking BYDUREON BCISE and seek medical advice promptly [see Warnings and Precautions (5.7) ] . 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) ]. Serious Injection-Site Reactions Inform patients that there have been postmarketing reports of serious injection-site reactions with or without subcutaneous nodules, with the use of BYDUREON. Isolated cases of injection-site reactions required surgical intervention. Advise patients to seek medical advice if symptomatic nodules occur, or for any signs or symptoms of abscess, cellulitis, or necrosis [see Warnings and Precautions (5.9) ] . Acute Gallbladder Disease Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up [see Warnings and Precautions (5.10)]. 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) ]. 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. Inform patients formerly on BYETTA who start BYDUREON BCISE that they may experience transient elevations in blood glucose concentrations, which generally improve within the first 4 weeks after initiation of therapy [see Dosage and Administration (2.1) ] . Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 By: Resilience US, Inc. West Chester, OH 45071 and Vetter Pharma-Fertigung GmbH & Co. KG 88214 Ravensburg Germany BYDUREON, BCISE and BYETTA are trademarks of the AstraZeneca group of companies.

Table 3: Clinically Relevant Interactions with BYDUREON BCISE Concomitant Use of Insulin Secretagogues or Insulin Clinical Impact Exenatide promotes insulin release from pancreatic beta-cells in the presence of elevated glucose concentrations. The risk of hypoglycemia is increased when exenatide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin [see Adverse Reactions (6.1) ] . Intervention When initiating BYDUREON BCISE, consider reducing the dose of concomitantly administered insulin secretagogue or insulin to reduce the risk of hypoglycemia. Warfarin Clinical Impact BYDUREON BCISE has not been studied with warfarin. However, in a drug interaction study, BYETTA did not have a significant effect on INR [see Clinical Pharmacology (12.3) ] . There have been postmarketing reports for exenatide of increased INR with concomitant use of warfarin, sometimes associated with bleeding [see Adverse Reactions (6.2) ] . Intervention In patients taking warfarin, the INR should be monitored more frequently after initiating BYDUREON BCISE. Once a stable INR has been documented, the INR can be monitored at the intervals recommended for patients taking warfarin. Orally Administered Drugs (e.g., acetaminophen) Clinical Impact Exenatide slows gastric emptying. Therefore, BYDUREON BCISE has the potential to reduce the rate of absorption of orally administered drugs [see Clinical Pharmacology (12.3) ]. Intervention Use caution when administering oral medications with BYDUREON BCISE where a slower rate of oral absorption may be clinically meaningful. • May impact absorption of orally administered medications. ( 7 ) • Warfarin: Postmarketing reports with exenatide of increased international normalized ratio (INR) sometimes associated with bleeding. Monitor INR frequently until stable upon initiation of BYDUREON BCISE therapy. ( 7 )

Risk Summary Limited data with exenatide, the active ingredient in BYDUREON BCISE, 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 (see Clinical Considerations) . Based on animal reproduction studies, there may be risks to the fetus from exposure to BYDUREON BCISE during pregnancy. BYDUREON BCISE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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 (see Data ). 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 HbA 1c >7 and has been reported to be as high as 20-25% in women with HbA 1c >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 Embryofetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery 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-, 8-, and 19-times human exposure, respectively, at the MRHD of 2 mg/week BYDUREON BCISE 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 BCISE, by subcutaneous injection twice a day. Differences in embryofetal 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 BCISE 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 6-times the human exposure from the MRHD of BYDUREON BCISE 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 at 6 mcg/kg/day 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 BCISE based on AUC comparison.

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

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) ].

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 Due to Volume Depletion [see Warnings and Precautions (5.4) ] • Severe Gastrointestinal Adverse Reactions [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) ] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.11) ] Most common (≥5%) in clinical trials: injection-site nodule, nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 and www.bydureonbcise.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 data in this section are derived from pooled data from the controlled period of the 2 comparator-controlled trials (Trials 1 and 2) in adults as well as data from the extension phase of one of these trials [see Clinical Studies (14.2) ] . There were 410 patients exposed to BYDUREON BCISE 2 mg for 28 weeks during the controlled phases, and an additional 116 patients exposed to BYDUREON BCISE 2 mg during an uncontrolled extension for an additional 24 weeks. Overall, there were 526 patients exposed to BYDUREON BCISE 2 mg with a mean duration of exposure of 35 weeks in the controlled and extension phases of the two trials. Across the treatment arms in the controlled periods, the mean age of patients was 55 years, 2% were 75 years or older and 59% were male. The population in these studies was 78% White, 15% Black or African American, 5% Asian; 1% American Indian or Alaska Native; <1 % were Native Hawaiian or Pacific Islander; and <1% were other races. This population included 42% of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.3 years and had a mean HbA 1c of 8.5%. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m 2 ) 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 (14.6) ]. Common Adverse Reactions Table 1 summarizes the adverse reactions with an incidence ≥5% occurring in BYDUREON BCISE-treated adult patients in the pooled data from the controlled and extension phases, including 10 weeks of follow‑up, of the two comparator-controlled 28-week clinical trials. Adverse reactions were identified based on known adverse reactions associated with BYDUREON. Table 1: Adverse Reactions Reported in ≥5% of BYDUREON BCISE-Treated Patients from Pooled Clinical Trial Data in Patients with Type 2 Diabetes Mellitus (Trials 1 and 2) BYDUREON BCISE 2 mg N=526 % Injection site nodule 10.5 Nausea 8.2 Note: Percentages are based on the number of patients who were randomized and received at least one dose of BYDUREON BCISE. Nausea was a common adverse reaction associated with initiation of treatment with BYDUREON BCISE and usually decreased over time with continued use. The incidence of nausea and/or vomiting was 2% in the first week of therapy compared to 1% in the 4th week of therapy. Less Common Adverse Reactions Adverse reactions that occurred in >2% and <5% of adult patients receiving BYDUREON BCISE during the controlled and extension phases, including 10 weeks of follow‑up, of the two comparator-controlled 28-week clinical trials include: headache (4.4%), diarrhea (4.0%), vomiting (3.4%), injection site pruritus (3.2%), dizziness (2.5%), injection site erythema (2.3%), constipation (2.1%). 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. The most common classes of adverse reactions leading to discontinuation of therapy for BYDUREON BCISE-treated patients were Gastrointestinal Disorders 2.0% and General Disorders and Administration Site Conditions 1.2%. For BYDUREON BCISE-treated patients, the most frequent adverse reactions leading to discontinuation of therapy within each of these respective classes were diarrhea (0.7%), nausea (0.7%), vomiting (0.5%) and injection-site nodule (0.5%). 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 Incidence of Hypoglycemia (glucose <54 mg/dL) Mono- or Combination Therapy with One or Two OADs Trial (28 weeks) With Concomitant Sulfonylurea Use BYDUREON BCISE 2 mg (N=88) 25% Without Concomitant Sulfonylurea Use BYDUREON BCISE 2 mg (N=141) 2.1% Add-On to Metformin Trial (28 weeks) All treated subjects BYDUREON BCISE 2 mg (N=181) 0.0% Incidence of Severe Hypoglycemia Mono- or Combination Therapy with One or Two OADs Trial (28 weeks) With Concomitant Sulfonylurea Use BYDUREON BCISE 2 mg (N=88) 2.3% Without Concomitant Sulfonylurea Use BYDUREON BCISE 2 mg (N=141) 0.7% Add-On to Metformin Trial (28 weeks) All treated subjects BYDUREON BCISE 2 mg (N=181) 0.0% Note: N and percentages are based on the number of patients who were randomized and received at least one dose of BYDUREON BCISE. 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 (14.6) ] , 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 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) ]. 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. Acute Pancreatitis In clinical trials of BYDUREON BCISE acute pancreatitis occurred in 0.4% of patients. Cholelithiasis and cholecystitis In the EXSCEL trial [see Clinical Studies (14.5) ] , 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of BYDUREON BCISE or other formulations of exenatide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal Blood : Drug induced thrombocytopenia. Drug Interactions : Increased international normalized ratio (INR) sometimes associated with bleeding, with concomitant warfarin [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. Hepatobiliary : Cholecystitis, cholelithiasis requiring cholecystectomy. 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. Neurologic : Dysgeusia, somnolence, dysesthesia. Pulmonary : Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. Renal : 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 : Alopecia.

Effects of overdoses with BYETTA, another exenatide product, included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations, including severe hypoglycemia requiring parenteral glucose administration. In the event of overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Initiate appropriate supportive treatment according to the patient's clinical signs and symptoms.