Byetta

5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including BYETTA. Discontinue if pancreatitis is suspected. ( 5.1 ) • Never share a BYETTA pen between patients, even if the needle is changed. ( 5.2 ) • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: Patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. Reduction in the dose of insulin secretagogues or insulin may be necessary. ( 5.3 ) • Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion ( 5.4 ) • Severe Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe. BYETTA is not recommended in patients with severe gastroparesis. ( 5.5 ) • Immunogenicity: Patients may develop antibodies to exenatide. If there is worsening glycemic control or failure to achieve target glycemic control, consider alternative antidiabetic therapy. ( 5.6 ) • Hypersensitivity: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue BYETTA and promptly seek medical advice. ( 5.7 ) • Drug-induced Immune-mediated Thrombocytopenia: Serious bleeding which may be fatal has been reported. Discontinue BYETTA promptly and avoid re-exposure to exenatide. ( 5.8 ) • Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.9 ) • Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.10 ) 5.1 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with glucagon-like peptide-1 (GLP-1) receptor agonists, including BYETTA [see Adverse Reactions (6.2) ] . After initiation of BYETTA, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue BYETTA and initiate appropriate management. 5.2 Never Share a BYETTA Pen Between Patients BYETTA pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving BYETTA in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia including severe hypoglycemia [see Adverse Reactions (6) and Drug Interactions (7) ] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.4 Acute Kidney Injury Due to Volume Depletion There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists, BYETTA [see Adverse Reactions (6.2) ] . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions (6) ] . Monitor renal function in patients reporting adverse reactions to BYETTA that could lead to volume depletion, especially during dosage initiation and escalation of BYETTA. BYETTA is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease and should be used with caution in patients with renal transplantation [see Use in Specific Populations (8.6) ] . 5.5 Severe Gastrointestinal Adverse Reactions Use of GLP-1 receptor agonists, including BYETTA, has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6) ] . BYETTA is not recommended in patients with severe gastroparesis. 5.6 Immunogenicity Patients may develop antibodies to exenatide following treatment with BYETTA. Antibody levels were measured in 90% of subjects in the 30-week, 24-week, and 16-week placebo-controlled studies and the 30-week comparator-controlled study of BYETTA. In 3%, 4%, 1%, and 1% of these patients, respectively, antibody formation was associated with an attenuated glycemic response. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered [see Adverse Reactions (6.1) ] . 5.7 Hypersensitivity There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) in patients treated with BYETTA. If a hypersensitivity reaction occurs, the patient should discontinue BYETTA and other suspect medications and promptly seek medical advice. Inform and closely monitor patients with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist for allergic reactions, because it is unknown whether such patients will be predisposed to anaphylaxis with BYETTA [see Adverse Reactions (6.2) ] . 5.8 Drug-Induced Thrombocytopenia Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported in the postmarketing setting with exenatide use. Drug-induced thrombocytopenia is an immune-mediated reaction, with exenatide-dependent anti-platelet antibodies. In the presence of exenatide, these antibodies cause platelet destruction. If drug-induced thrombocytopenia is suspected, discontinue BYETTA immediately and do not re-expose the patient to exenatide [see Adverse Reactions (6.2) ] . 5.9 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 a clinical study with exenatide, 1.9% of exenatide-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated. 5.10 Pulmonary Aspiration During General Anesthesia or Deep Sedation BYETTA delays gastric emptying [ see Clinical Pharmacology (12.2) ]. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking BYETTA, including whether modifying preoperative fasting recommendations or temporarily discontinuing BYETTA could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking BYETTA.

5.1 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with glucagon-like peptide-1 (GLP-1) receptor agonists, including BYETTA [see Adverse Reactions (6.2) ] . After initiation of BYETTA, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue BYETTA and initiate appropriate management.

5.2 Never Share a BYETTA Pen Between Patients BYETTA pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.

5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving BYETTA in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia including severe hypoglycemia [see Adverse Reactions (6) and Drug Interactions (7) ] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Acute Pancreatitis [see Warnings and Precautions (5.1) ] • Never Share a BYETTA Pen Between Patients [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 [see Warnings and Precautions (5.6) ] • Hypersensitivity [see Warnings and Precautions (5.7) ] • Drug-Induced Thrombocytopenia [see Warnings and Precautions (5.8) ] • Acute Gallbladder Disease [see Warnings and Precautions (5.9) ] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.10) ] • Most common (≥5%) and occurring more frequently than placebo in clinical trials: nausea, hypoglycemia, vomiting, diarrhea, feeling jittery, dizziness, headache, dyspepsia, constipation, asthenia. Nausea usually decreases over time. ( 5.3 , 6 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 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. Hypoglycemia Table 1 summarizes the incidence and rate of hypoglycemia with BYETTA in six placebo-controlled clinical trials. Table 1: Incidence (%) and Rate of Hypoglycemia when BYETTA was used as Monotherapy or with Concomitant Antidiabetic Therapy in Six Placebo-Controlled Clinical Trials A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a documented blood glucose value <54 mg/dL or prompt recovery after treatment for hypoglycemia. Placebo BID BYETTA 5 mcg BID BYETTA 10 mcg BID Monotherapy (24 Weeks) N 77 77 78 % Overall 1.3% 5.2% 3.8% Rate (episodes/patient-year) 0.03 0.21 0.52 % Severe 0.0% 0.0% 0.0% With Metformin (30 Weeks) N 113 110 113 % Overall 5.3% 4.5% 5.3% Rate (episodes/patient-year) 0.12 0.13 0.12 % Severe 0.0% 0.0% 0.0% With a Sulfonylurea (30 Weeks) N 123 125 129 % Overall 3.3% 14.4% 35.7% Rate (episodes/patient-year) 0.07 0.64 1.61 % Severe 0.0% 0.0% 0.0% With Metformin and a Sulfonylurea (30 Weeks) N 247 245 241 % Overall 12.6% 19.2% 27.8% Rate (episodes/patient-year) 0.58 0.78 1.71 % Severe 0.0% 0.4% 0.0% With a Thiazolidinedione (16 Weeks) N 112 not evaluated 121 % Overall 7.1% not evaluated 10.7% Rate (episodes/patient-years) 0.56 not evaluated 0.98 % Severe 0.0% not evaluated 0.0% With Insulin Glargine with or without Metformin and/or Thiazolidinedione (30 Weeks) When BYETTA was initiated in combination with insulin glargine, the dose of insulin glargine was decreased by 20% in patients with an HbA 1c ≤8.0% to minimize the risk of hypoglycemia. See Table 9 for insulin dose titration algorithm. N 122 not evaluated 137 % Overall 29.5% not evaluated 24.8% Rate (episodes/patient-years) 1.58 not evaluated 1.61 % Severe 0.8% not evaluated 0.0% N = number of Intent-to-Treat subjects in each treatment group. Immunogenicity Antibodies were assessed in 90% of subjects in the 30-week, 24-week, and 16-week studies of BYETTA. In the 30-week controlled trials of BYETTA add-on to metformin and/or sulfonylurea, antibodies were assessed at 2- to 6-week intervals. The mean antibody titer peaked at Week 6 and was reduced by 55% by Week 30. Three hundred and sixty patients (38%) had low titer antibodies (<625) to exenatide at 30 weeks. The level of glycemic control (HbA 1c ) in these patients was generally comparable to that observed in the 534 patients (56%) without antibody titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at 30 weeks. Of these patients, 32 (3% overall) had an attenuated glycemic response to BYETTA; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without antibodies. In the 16-week trial of BYETTA add-on to thiazolidinediones, with or without metformin, 36 patients (31%) had low titer antibodies to exenatide at 16 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 69 patients (60%) without antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks. Of these patients, 4 (4% overall) had an attenuated glycemic response to BYETTA; the remaining 6 (5% overall) had a glycemic response comparable to that of patients without antibodies. In the 24-week trial of BYETTA used as monotherapy, 40 patients (28%) had low titer antibodies to exenatide at 24 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 101 patients (70%) without antibody titers. An additional 3 patients (2%) had higher titer antibodies at 24 weeks. Of these patients, 1 (1% overall) had an attenuated glycemic response to BYETTA; the remaining 2 (1% overall) had a glycemic response comparable to that of patients without antibodies. Antibodies to exenatide were not assessed in the 30-week placebo-controlled trial of BYETTA used in combination with insulin glargine. In the 30-week comparator-controlled trial of BYETTA used in combination with insulin glargine and metformin, 60 patients (20%) had low titer antibodies to exenatide at 30 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 234 patients (77%) without antibody titers. An additional 10 patients (3%) had higher titer antibodies at 30 weeks. Of these patients, 2 (1% overall) had an attenuated glycemic response to BYETTA; the remaining 8 (3% overall) had a glycemic response comparable to that of patients without antibodies. Two hundred and ten patients with antibodies to exenatide in the BYETTA 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. Other Adverse Reactions Monotherapy For the 24-week placebo-controlled study of BYETTA used as a monotherapy, Table 2 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients. Table 2: Treatment-Emergent Adverse Reactions ≥2% Incidence with BYETTA used as Monotherapy (excluding Hypoglycemia) In a 24-week placebo-controlled trial. Monotherapy Placebo BID N=77 % All BYETTA BID N=155 % Nausea 0 8 Vomiting 0 4 Dyspepsia 0 3 BID = twice daily. Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite, diarrhea, and dizziness. The most frequently reported adverse reaction associated with BYETTA, nausea, occurred in a dose-dependent fashion. Two of the 155 patients treated with BYETTA withdrew due to adverse reactions of headache and nausea. No placebo-treated patients withdrew due to adverse reactions. Cholelithiasis and cholecystitis In a clinical study with exenatide, 1.9% of exenatide-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis. Combination Therapy Add-On to Metformin and/or Sulfonylurea In the three 30-week controlled trials of BYETTA add-on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients are summarized in Table 3. Table 3: Treatment-Emergent Adverse Reactions ≥2% Incidence and Greater Incidence with BYETTA Treatment used with Metformin and/or a Sulfonylurea (excluding Hypoglycemia) In three 30-week placebo-controlled clinical trials. Placebo BID N=483 % All BYETTA BID N=963 % Nausea 18 44 Vomiting 4 13 Diarrhea 6 13 Feeling Jittery 4 9 Dizziness 6 9 Headache 6 9 Dyspepsia 3 6 Asthenia 2 4 Gastroesophageal Reflux Disease 1 3 Hyperhidrosis 1 3 BID = twice daily Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite. Nausea was the most frequently reported adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced nausea. Patients in the long-term uncontrolled open-label extension studies at 52 weeks reported no new types of adverse reactions than those observed in the 30-week controlled trials. The most common adverse reactions leading to withdrawal for BYETTA-treated patients were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew due to nausea and none due to vomiting. Add-On to Thiazolidinedione with or without Metformin For the 16-week placebo-controlled study of BYETTA add-on to a thiazolidinedione, with or without metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with an incidence of ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients. Table 4: Treatment-Emergent Adverse Reactions ≥2% Incidence with BYETTA used with a Thiazolidinedione (TZD), with or without Metformin (MET) (excluding Hypoglycemia) In a 16-week placebo-controlled clinical trial. With a TZD or TZD/MET Placebo N=112 % All BYETTA BID N=121 % Nausea 15 40 Vomiting 1 13 Dyspepsia 1 7 Diarrhea 3 6 Gastroesophageal Reflux Disease 0 3 BID = twice daily. Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite. Chills (n=4) and injection-site reactions (n=2) occurred only in BYETTA-treated patients. The two patients who reported an injection-site reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic hypersensitivity pneumonitis) were reported in the BYETTA arm. No serious adverse events were reported in the placebo arm. The most common adverse reactions leading to withdrawal for BYETTA-treated patients were nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to nausea. Add-On to Insulin Glargine with or without Metformin and/or Thiazolidinedione (Placebo-Controlled) For the 30-week placebo-controlled study of BYETTA as add-on to insulin glargine with or without oral antihyperglycemic medications, Table 5 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients. Table 5: Treatment-Emergent Adverse Reactions ≥2% Incidence with BYETTA used with Insulin Glargine with or without Oral Antihyperglycemic Medications (excluding Hypoglycemia) In a 30-week placebo-controlled clinical trial. With Insulin Glargine Placebo N=122 % All BYETTA BID N=137 % Nausea 8 41 Vomiting 4 18 Diarrhea 8 18 Headache 4 14 Constipation 2 10 Dyspepsia 2 7 Asthenia 1 5 Abdominal Distension 1 4 Decreased Appetite 0 3 Flatulence 1 2 Gastroesophageal Reflux Disease 1 2 BID = twice daily. The most frequently reported adverse reactions leading to withdrawal for BYETTA-treated patients were nausea (5.1%) and vomiting (2.9%). No placebo-treated patients withdrew due to nausea or vomiting. 6.2 Postmarketing Experience The following additional adverse reactions have been reported during post approval use of BYETTA 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 : Drug induced thrombocytopenia. Drug Interactions : International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding [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, 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.

<table cellpadding="5.75pt" width="100%"><caption>Table 1: Incidence (%) and Rate of Hypoglycemia when BYETTA was used as Monotherapy or with Concomitant Antidiabetic Therapy in Six Placebo-Controlled Clinical Trials<footnote ID="_Ref534175088">A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a documented blood glucose value &lt;54 mg/dL or prompt recovery after treatment for hypoglycemia.</footnote></caption><col width="44%"/><col width="14%"/><col width="21%"/><col width="20%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">BID</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">BYETTA</content> <content styleCode="bold">5 mcg BID</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">BYETTA</content> <content styleCode="bold">10 mcg BID</content></paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Monotherapy (24 Weeks)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> N</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>77</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>77</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>78</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> % Overall</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rate (episodes/patient-year)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.03</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.21</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.52</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> % Severe</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">With Metformin (30 Weeks)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> N</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>113</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>110</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>113</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> % Overall</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.5%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rate (episodes/patient-year)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.12</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.13</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.12</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> % Severe</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">With a Sulfonylurea (30 Weeks)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> N</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>123</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>125</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>129</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> % Overall</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14.4%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>35.7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rate (episodes/patient-year)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.07</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.64</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.61</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> % Severe</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">With Metformin and a Sulfonylurea (30 Weeks)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> N</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>247</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>245</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>241</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> % Overall</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12.6%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19.2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>27.8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rate (episodes/patient-year)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.58</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.78</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.71</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> % Severe</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.4%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">With a Thiazolidinedione (16 Weeks)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> N</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>112</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>not evaluated</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>121</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> % Overall</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7.1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>not evaluated</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10.7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rate (episodes/patient-years)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.56</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>not evaluated</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.98</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> % Severe</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>not evaluated</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">With Insulin Glargine with or without Metformin and/or Thiazolidinedione (30 Weeks)</content><footnote ID="_Ref534175284">When BYETTA was initiated in combination with insulin glargine, the dose of insulin glargine was decreased by 20% in patients with an HbA_1c &#x2264;8.0% to minimize the risk of hypoglycemia. See Table 9 for insulin dose titration algorithm.</footnote></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> N</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>122</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>not evaluated</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>137</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> % Overall</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>29.5%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>not evaluated</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>24.8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rate (episodes/patient-years)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.58</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>not evaluated</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.61</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> % Severe</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.8%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>not evaluated</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.0%</paragraph></td></tr><tr><td colspan="4" styleCode="Toprule " valign="top"><paragraph>N = number of Intent-to-Treat subjects in each treatment group.</paragraph></td></tr></tbody></table>

<table width="100%"><caption>Table 2: Treatment-Emergent Adverse Reactions &#x2265;2% Incidence with BYETTA used as Monotherapy (excluding Hypoglycemia)<footnote ID="_Ref516116753">In a 24-week placebo-controlled trial.</footnote></caption><col width="31%"/><col width="29%"/><col width="40%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Monotherapy</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Placebo BID</content> <content styleCode="bold">N=77</content> <content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">All BYETTA BID</content> <content styleCode="bold">N=155</content> <content styleCode="bold">%</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Dyspepsia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph>BID = twice daily.</paragraph></td></tr></tbody></table>

<table width="100%"><caption>Table 3: Treatment-Emergent Adverse Reactions &#x2265;2% Incidence and Greater Incidence with BYETTA Treatment used with Metformin and/or a Sulfonylurea (excluding Hypoglycemia)<footnote ID="_Ref516117126">In three 30-week placebo-controlled clinical trials.</footnote></caption><col width="49%"/><col width="22%"/><col width="29%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Placebo BID</content> <content styleCode="bold">N=483</content> <content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">All BYETTA BID</content> <content styleCode="bold">N=963</content> <content styleCode="bold">%</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>44</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Feeling Jittery</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dizziness</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyspepsia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Asthenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gastroesophageal Reflux Disease</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hyperhidrosis</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph>BID = twice daily</paragraph></td></tr></tbody></table>