Indications and uses
1 INDICATIONS AND USAGE BYETTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use • BYETTA contains exenatide. Coadministration with other exenatide-containing products is not recommended. BYETTA (exenatide) is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 , 14 ) Limitations of Use • Coadministration with other exenatide-containing products is not recommended ( 1 ).
Dosing and administration
2 DOSAGE AND ADMINISTRATION • Inject subcutaneously within 60 minutes prior to morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). ( 2.1 ) • Initiate at 5 mcg per dose twice daily; increase to 10 mcg twice daily after 1 month based on clinical response. ( 2.1 ) 2.1 Recommended Dosing • Initiate BYETTA at 5 mcg administered subcutaneously twice daily at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Do not administer after a meal. • Based on clinical response, the dose of BYETTA can be increased to 10 mcg twice daily which is recommended after 1 month of therapy, in order to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ] . • Administer as a subcutaneous injection in the thigh, abdomen, or upper arm. • Rotate injections sites with each dose. Do not use the same site for each injection. • Inspect visually for particulate matter and discoloration. Only use BYETTA if the solution appears clear, colorless, and contains no particles. • When using BYETTA with insulin, administer as separate injections and never mix. It is acceptable to inject BYETTA and insulin in the same body region, but the injections should not be adjacent to each other. • If a dose is missed, resume the treatment regimen as prescribed with the next scheduled dose.
2.1 Recommended Dosing • Initiate BYETTA at 5 mcg administered subcutaneously twice daily at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Do not administer after a meal. • Based on clinical response, the dose of BYETTA can be increased to 10 mcg twice daily which is recommended after 1 month of therapy, in order to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ] . • Administer as a subcutaneous injection in the thigh, abdomen, or upper arm. • Rotate injections sites with each dose. Do not use the same site for each injection. • Inspect visually for particulate matter and discoloration. Only use BYETTA if the solution appears clear, colorless, and contains no particles. • When using BYETTA with insulin, administer as separate injections and never mix. It is acceptable to inject BYETTA and insulin in the same body region, but the injections should not be adjacent to each other. • If a dose is missed, resume the treatment regimen as prescribed with the next scheduled dose.
Warnings and precautions
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.
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) ] .
Drug interactions
7 DRUG INTERACTIONS • May impact absorption of orally administered medications. ( 7 ) • Warfarin: Postmarketing reports of increased INR sometimes associated with bleeding. Monitor INR frequently until stable upon initiation or alteration of BYETTA therapy. ( 7 ) Generic Section Table 6: Clinically Relevant Interactions with BYETTA 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 Warnings and Precautions (5.3) and Adverse Reactions (6) ] . Intervention When initiating BYETTA, consider reducing the dose of concomitantly administered insulin secretagogue or insulin to reduce the risk of hypoglycemia. Warfarin Clinical Impact 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 BYETTA of increased INR with concomitant use of warfarin, sometimes associated with bleeding [see Adverse Reactions (6.2) ] . Intervention In patients taking warfarin, the prothrombin time should be monitored more frequently after initiation or alteration of BYETTA therapy. Once a stable prothrombin time has been documented, the prothrombin time can be monitored at the intervals recommended for patients taking warfarin. Orally Administered Drugs (e.g., acetaminophen) Clinical Impact Exenatide slows gastric emptying. Therefore, BYETTA 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 BYETTA where a slower rate of oral absorption may be clinically meaningful. For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before BYETTA injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when BYETTA is not administered [see Clinical Pharmacology (12.3) ] .
Adverse reactions
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.
Clinical studies
14 CLINICAL STUDIES BYETTA has been studied 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, or in combination with insulin glargine with or without metformin and/or thiazolidinedione. 14.1 Monotherapy In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, BYETTA 5 mcg BID (n=77), BYETTA 10 mcg BID (n=78), or placebo BID (n=77) was used as monotherapy in patients with entry HbA1c ranging from 6.5% to 10%. All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. BYETTA or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were White, 26% were West Asian, 3% were Hispanic or Latino ethnicity, 3% were Black or African American, and 0.4% were of East Asian ethnicity. The primary endpoint was the change in HbA 1c from baseline to Week 24 (or the last value at time of early discontinuation). Compared to placebo, BYETTA 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in HbA 1c from baseline at Week 24 (Table 7). Table 7: Results of 24-Week Placebo-Controlled Trial of BYETTA used as Monotherapy Placebo BID BYETTA 5 mcg BID BYETTA 10 mcg BYETTA 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 5 months before the morning and evening meals. BID Intent-to-Treat Population (N) 77 77 78 HbA 1c (%), Mean Baseline 7.8 7.9 7.8 Change at Week 24 Least squares means are adjusted for screening HbA1c strata and baseline value of the dependent variable. −0.2 −0.7 −0.9 Difference from placebo (95% CI) −0.5 [−0.9, −0.2] p <0.01, treatment vs. placebo. −0.7 [−1.0, −0.3] Proportion Achieving HbA 1c <7% 38% 48% 53% Body Weight (kg), Mean Baseline 86.1 85.1 86.2 Change at Week 24 −1.5 −2.7 −2.9 Difference from placebo (95% CI) −1.3 [−2.3, −0.2] −1.5 [−2.5, −0.4] Fasting Serum Glucose Measured using the hexokinase-based glucose method. (mg/dL), Mean Baseline 159 166 155 Change at Week 24 −5 −17 −19 Difference from placebo (95% CI) −12 [−23.2, −1.3] −14 [−24.5, −2.5] BID = twice daily. On average, there were no adverse effects of exenatide on blood pressure or lipids. 14.2 Combination Therapy with Oral Antihyperglycemic Medicines Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of BYETTA in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea. In addition, a 16-week, placebo-controlled trial was conducted where BYETTA was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control. In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned to receive BYETTA 5 mcg BID, BYETTA 10 mcg BID, or placebo BID before the morning and evening meals, in addition to their existing oral antidiabetic agent. All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the study. A total of 1446 patients were randomized in the three 30-week trials: 991 (69%) were White, 224 (16%) were Hispanic or Latino and 174 (12%) were of Black of African American ethnicity. Mean HbA1c values at baseline for the trials ranged from 8.2% to 8.7%. In the placebo-controlled trial of 16 weeks duration, BYETTA (n=121) or placebo (n=112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin. Randomization to BYETTA or placebo was stratified based on whether the patients were receiving metformin. BYETTA treatment was initiated at a dose of 5 mcg BID for 4 weeks then increased to 10 mcg BID for 12 more weeks. Patients assigned to placebo received placebo BID throughout the study. BYETTA or placebo was injected subcutaneously before the morning and evening meals. In this trial, 79% of patients were taking a thiazolidinedione and metformin and 21% were taking a thiazolidinedione alone. The majority of patients (84%) were White, 8% were Hispanic or Latino ethnicity, and 3% were of Black or African American ethnicity. The mean baseline HbA1c values were 7.9% for BYETTA and placebo. The primary endpoint in each study was the mean change in HbA 1c from baseline to study end (or early discontinuation). Table 8 summarizes the study results for the 30- and 16-week clinical trials. Table 8: Results of 30-Week and 16-Week Placebo-Controlled Trials of BYETTA used in Combination with Oral Antidiabetic Agents Placebo BID BYETTA 5 mcg BID BYETTA 10 mcg BYETTA 5 mcg twice daily for 1 month followed by 10 mcg BID for 6 months for the 30-week trials or 10 mcg BID for 3 months in the 16-week trial before the morning and evening meals. BID In Combination with Metformin (30 Weeks) Intent-to-Treat Population (N) 113 110 113 HbA 1c (%), Mean Baseline 8.2 8.3 8.2 Change at Week 30 Least squares means are adjusted for baseline HbA 1c strata or value, investigator site, baseline value of the dependent variable (if applicable), and background antihyperglycemic therapy (if applicable). −0.0 −0.5 −0.9 Difference from placebo (95% CI) −0.5 [−0.7, −0.2] p <0.01, treatment vs. placebo. −0.9 [−1.1, −0.6] Proportion Achieving HbA 1c <7% 12% 32% 40% Body Weight (kg), Mean Baseline 99.9 100.0 100.9 Change at Week 30 −0.2 −1.3 −2.6 Difference from placebo (95% CI) −1.1 [−2.2, −0.0] −2.4 [−3.5, −1.3] Fasting Plasma Glucose Measured using the hexokinase-based glucose method. (mg/dL), Mean Baseline 169 176 168 Change at Week 30 +14 −5 −10 Difference from placebo (95% CI) −20 [−32, −7] −24 [−37, −12] In Combination with a Sulfonylurea (30 Weeks) Intent-to-Treat Population (N) 123 125 129 HbA 1c (%), Mean Baseline 8.7 8.5 8.6 Change at Week 30 +0.1 −0.5 −0.9 Difference from placebo (95% CI) −0.6 [−0.9, −0.3] −1.0 [−1.3, −0.7] Proportion Achieving HbA 1c <7% 10% 25% 36% Body Weight (kg), Mean Baseline 99.1 94.9 95.2 Change at Week 30 −0.8 −1.1 −1.6 Difference from placebo (95% CI) −0.3 [−1.1, 0.6] −0.9 [−1.7, −0.0] Fasting Plasma Glucose (mg/dL), Mean Baseline 194 180 178 Change at Week 30 +6 −5 −11 Difference from placebo (95% CI) −11 [−25, 3] −17 [−30, −3] In Combination with Metformin and a Sulfonylurea (30 Weeks) Intent-to-Treat Population (N) 247 245 241 HbA 1c (%), Mean Baseline 8.5 8.5 8.5 Change at Week 30 +0.1 −0.7 −0.9 Difference from placebo (95% CI) −0.8 [−1.0, −0.6] −1.0 [−1.2, −0.8] Proportion Achieving HbA 1c <7% 8% 25% 31% Body Weight (kg), Mean Baseline 99.1 96.9 98.4 Change at Week 30 −0.9 −1.6 −1.6 Difference from placebo (95% CI) −0.7 [−1.2, −0.2] −0.7 [−1.3, −0.2] Fasting Plasma Glucose (mg/dL), Mean Baseline 181 182 178 Change at Week 30 +13 −11 −12 Difference from placebo (95% CI) −24 [−33, −15] −25 [−34, −16] In Combination with a Thiazolidinedione or a Thiazolidinedione plus Metformin (16 Weeks) Intent-to-Treat Population (N) 112 Dose not studied 121 HbA 1c (%), Mean Baseline 7.9 Dose not studied 7.9 Change at Week 16 +0.1 Dose not studied −0.7 Difference from placebo (95% CI) Dose not studied −0.9 [−1.1, −0.7] Proportion Achieving HbA 1c <7% 15% Dose not studied 51% Body Weight (kg), Mean Baseline 96.8 Dose not studied 97.5 Change at Week 16 −0.0 Dose not studied −1.5 Difference from placebo (95% CI) Dose not studied −1.5 [−2.2, −0.7] Fasting Serum Glucose (mg/dL), Mean Baseline 159 Dose not studied 164 Change at Week 16 +4 Dose not studied −21 Difference from placebo (95% CI) Dose not studied −25 [−33, −16] BID = twice daily. HbA 1c The addition of BYETTA to a regimen of metformin, a sulfonylurea, or both, resulted in statistically significant reductions from baseline in HbA 1c compared with patients receiving placebo added to these agents in the three controlled trials (Table 8). In the 16-week trial of BYETTA add-on to thiazolidinediones, with or without metformin, BYETTA resulted in statistically significant reductions from baseline in HbA 1c compared with patients receiving placebo (Table 8). Postprandial Glucose Postprandial glucose was measured after a mixed meal tolerance test in 9.5% of patients participating in the 30-week add-on to metformin, add-on to sulfonylurea, and add-on to metformin in combination with sulfonylurea clinical trials. In this pooled subset of patients, BYETTA reduced postprandial plasma glucose concentrations in a dose-dependent manner. The mean (SD) change in 2-hour postprandial glucose concentration following administration of BYETTA at Week 30 relative to baseline was − 63 (65) mg/dL for 5 mcg BID (n=42), − 71 (73) mg/dL for 10 mcg BID (n=52), and +11 (69) mg/dL for placebo BID (n=44). 14.3 Combination with Insulin Glargine 30-Week Placebo-Controlled Trial A 30-week, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of BYETTA (n=137) versus placebo (n=122) when added to titrated insulin glargine, with or without metformin and/or thiazolidinedione, in patients with type 2 diabetes with inadequate glycemic control. All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients assigned to BYETTA had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. BYETTA or placebo was injected subcutaneously before the morning and evening meals. Patients with an HbA1c ≤8.0% decreased their prestudy dose of insulin glargine by 20% and patients with an HbA1c ≥8.1% maintained their current dose of insulin glargine. Five weeks after initiating randomized treatment, insulin doses were titrated with guidance from the investigator toward predefined fasting glucose targets according to the dose titration algorithm provided in Table 9. The majority of patients (78%) were White, 10% were American Indian or Alaska Native, 9% were Black or African American, 3% were Asian, and 0.8% were of multiple origins. The primary endpoint was the change in HbA1c from baseline to Week 30. Compared to placebo, BYETTA 10 mcg BID resulted in statistically significant reductions in HbA1c from baseline at Week 30 (Table 9) in patients receiving titrated insulin glargine. Table 9: 30-Week Placebo-Controlled Trial of BYETTA Used in Combination with Insulin Glargine with or without Metformin and/or Thiazolidinediones Placebo BID + Titrated Insulin Glargine BYETTA 10 mcg BYETTA 5 mcg twice daily for 1 month followed by 10 mcg BID for 5 months for the 30-week trial. BID + Titrated Insulin Glargine Intent-to-Treat Population (N) 122 137 HbA 1c (%), Mean Baseline 8.5 8.3 Change at Week 30 Least squares means are based on a mixed model adjusting for treatment, pooled investigator, visit, baseline HbA 1c value, and treatment by visit, where subject is treated as a random effect. −1.0 −1.7 Difference from placebo (95% CI) −0.7 [−1.0, −0.5] p <0.01, treatment vs. placebo. Proportion Achieving HbA 1c <7% 29% 56% Body Weight (kg), Mean Baseline 93.8 95.4 Change at Week 30 Least squares means are based on a mixed model adjusting for treatment, pooled investigator, visit, baseline HbA 1c stratum, baseline value of the dependent variable (where applicable), and treatment by visit, where subject is treated as a random effect. 1.0 −1.8 Difference from placebo (95% CI) −2.7 [−3.7, −1.7] Fasting Serum Glucose Patients in both groups titrated insulin glargine dose to achieve optimal fasting glucose concentrations. (mg/dL), Mean Baseline 133 132 Change at Week 30 −16 −23 Difference from placebo (95% CI) −7 [−18, 3] BID = twice daily. Table 10: Dosing Algorithm for Titration of Insulin Glargine Adapted from Riddle et al. 2003. Fasting Plasma Glucose Values (mg/dL) Dose Change (U) <56 Value for at least 1 fasting plasma glucose measurement since the last assessment. − 4 56 to 72 − 2 73 to 99 Based on the average of fasting plasma glucose measurements taken over the prior 3 to 7 days. The increase in the total daily dose should not have exceeded more than 10 units per day or 10% of the current total daily dose, whichever was greater. 0 100 to 119 +2 120 to 139 +4 140 to 179 +6 ≥180 +8 Abbreviations: U = units. 30-Week Comparator-Controlled Noninferiority Trial A 30 week, open-label, active comparator-controlled, noninferiority study was conducted to evaluate the safety and efficacy of BYETTA (n=315) versus titrated insulin lispro (n=312) on a background of optimized basal insulin glargine and metformin in patients with type 2 diabetes with inadequate glycemic control. Following a 12-week basal insulin optimization (BIO) phase, subjects with an HbA 1c >7.0% entered a 30-week intervention phase and were randomized to add either BYETTA or insulin lispro to their existing regimen of insulin glargine and metformin. Insulin glargine was titrated to a target fasting plasma glucose of 72 to 100 mg/dL. All patients assigned to BYETTA initially received 5 mcg BID for four weeks. After four weeks, their dose was increased to 10 mcg BID. Patients in the BYETTA-treated arm with an HbA 1c ≤8.0% at the end of the BIO phase decreased their insulin glargine dose by at least 10%. All patients assigned to insulin lispro three times daily (TID) maintained their prior total daily insulin dose at baseline; however, the initial insulin lispro dose was ⅓ to ½ of the total daily insulin dose with the insulin glargine dose reduced accordingly. The insulin lispro dose was titrated based on preprandial glucose values. The majority of patients (87%) were White, 7% were American Indian or Alaska Native, 5% were Asian, and <1% were of Black or African American ethnicity. The primary endpoint was the change in HbA 1c from baseline to Week 30. Both BYETTA 10 mcg BID and titrated lispro provided a mean reduction in HbA 1c at Week 30 that met the pre-specified non-inferiority margin of 0.4%. Table 11: 30-Week Comparator-Controlled Trial of BYETTA used in Combination with Insulin Glargine and Metformin Titrated Insulin Lispro TID + Titrated Insulin Glargine BYETTA 10 mcg BYETTA 5 mcg BID for 1 month followed by 10 mcg BID for 5 months for the 30-week trial. BID + Titrated Insulin Glargine Intent-to-Treat Population (N) 312 315 HbA 1c (%), Mean Baseline 8.2 8.3 Change at Week 30 Least squares means are based on a mixed model adjusting for treatment, country, prior use of sulfonylurea (yes/no), visit, corresponding baseline, and treatment by visit interaction, where subject is treated as a random effect. Data at 30 weeks are available from 88% and 84% of the intent-to-treat subjects in the Lispro and BYETTA groups, respectively. −1.1 −1.1 Difference from Insulin Lispro (95% CI) −0.0 [−0.2, 0.1] Body Weight (kg), Mean Baseline 89.3 89.9 Change at Week 30 1.9 −2.6 Difference from Insulin Lispro (95% CI) −4.5 [−5.2, −3.9] Fasting Serum Glucose Patients titrated insulin glargine or insulin lispro dose to achieve prespecified target fasting and preprandial glucose concentrations. (mg/dL), Mean Baseline 126 130 Change at Week 30 5 −7 Difference from Insulin Lispro (95% CI) −12 [−19, −4] BID = twice daily. TID = three times daily.