EXENATIDE: 31,297 Adverse Event Reports & Safety Profile

Exenatide is a synthetic peptide, GLP-1 receptor agonist, that was originally identified in the lizard Heloderma suspectum . Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula C 184 H 282 N 50 O 60 S and 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 injection, USP is supplied for subcutaneous administration as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, USP; 2.2 mg metacresol as an antimicrobial preservative; mannitol as a tonicity-adjusting agent; and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg per dose or 10 mcg per dose. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID). Each prefilled device is filled with volume to allow delivery of 1.2 mL or 2.4 mL. Each device contains additional volume to allow for troubleshooting the device 4 times.

AND USAGE Exenatide injection is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Exenatide injection 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 Co-administration with other exenatide-containing products is not recommended. ( 1 ) Limitations of Use Exenatide injection contains exenatide. Co-administration with other exenatide-containing products is not recommended.

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.

Exenatide injection is contraindicated in patients with: A prior severe hypersensitivity reaction to exenatide or to any of the excipients in exenatide injection. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with exenatide injection [see Warnings and Precautions (5.7) ] . A history of drug-induced immune-mediated thrombocytopenia from exenatide products. Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported with exenatide use [see Warnings and Precautions (5.8) ]. History of severe hypersensitivity to exenatide or any of the excipients in exenatide injection. ( 4 ) History of drug-induced immune-mediated thrombocytopenia from exenatide products. ( 4 )

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 an Exenatide 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 Amneal Pharmaceuticals LLC at 1-877-835-5472 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 exenatide in six placebo-controlled clinical trials.

Table

1: Incidence (%) and Rate of Hypoglycemia when Exenatide was used as Monotherapy or with Concomitant Antidiabetic Therapy in Six Placebo-Controlled Clinical Trials * Placebo BID Exenatide 5 mcg BID Exenatide 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) † 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% * 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. † When exenatide 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

10 for insulin dose titration algorithm. 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 exenatide. In the 30-week controlled trials of exenatide 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 exenatide; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without antibodies. In the 16-week trial of exenatide 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 exenatide; the remaining 6 (5% overall) had a glycemic response comparable to that of patients without antibodies. In the 24-week trial of exenatide 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 exenatide; 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 exenatide used in combination with insulin glargine. In the 30-week comparator-controlled trial of exenatide 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 exenatide; 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 exenatide 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 exenatide used as a monotherapy, Table 2 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥ 2% and occurring more frequently in exenatide-treated patients compared with placebo-treated patients.

Table

2: Treatment-Emergent Adverse Reactions ≥ 2% Incidence with Exenatide used as Monotherapy (excluding Hypoglycemia) * Monotherapy Placebo BID N=77 % All Exenatide BID N=155 % Nausea 0 8 Vomiting 0 4 Dyspepsia 0 3 * In a 24-week placebo-controlled trial. BID = twice daily. Adverse reactions reported in ≥ 1.0% to < 2.0% of patients receiving exenatide and reported more frequently than with placebo included decreased appetite, diarrhea and dizziness. The most frequently reported adverse reaction associated with exenatide, nausea, occurred in a dose-dependent fashion. Two of the 155 patients treated with exenatide 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 exenatide add-on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence ≥ 2% and occurring more frequently in exenatide-treated patients compared with placebo-treated patients are summarized in Table 3.

Table

3: Treatment-Emergent Adverse Reactions ≥ 2% Incidence and Greater Incidence with Exenatide Treatment used with Metformin and/or a Sulfonylurea (excluding Hypoglycemia) * Placebo BID N=483 % All Exenatide 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 * In three 30-week placebo-controlled clinical trials. BID = twice daily. Adverse reactions reported in ≥ 1.0% to < 2.0% of patients receiving exenatide 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 exenatide-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 exenatide 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 exenatide-treated patients compared with placebo-treated patients.

Table

4: Treatment-Emergent Adverse Reactions ≥ 2% Incidence with Exenatide used with a Thiazolidinedione (TZD), with or without Metformin (MET) (excluding Hypoglycemia) * With a TZD or TZD/MET Placebo N=112 % All Exenatide BID N=121 % Nausea 15 40 Vomiting 1 13 Dyspepsia 1 7 Diarrhea 3 6 Gastroesophageal Reflux Disease 0 3 * In a 16-week placebo-controlled clinical trial. BID = twice daily. Adverse reactions reported in ≥ 1.0% to < 2.0% of patients receiving exenatide and reported more frequently than with placebo included decreased appetite. Chills (n=4) and injection-site reactions (n=2) occurred only in exenatide-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 exenatide arm. No serious adverse events were reported in the placebo arm. The most common adverse reactions leading to withdrawal for exenatide-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 exenatide 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 exenatide-treated patients compared with placebo-treated patients.

Table

5: Treatment-Emergent Adverse Reactions ≥ 2% Incidence with Exenatide used with Insulin Glargine with or without Oral Antihyperglycemic Medications (excluding Hypoglycemia) * With Insulin Glargine Placebo N=122 % All Exenatide 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 * In a 30-week placebo-controlled clinical trial. BID = twice daily. The most frequently reported adverse reactions leading to withdrawal for exenatide-treated patients were nausea (5.1%) and vomiting (2.9%). No placebo-treated patients withdrew due to nausea or vomiting.

6.2 Post-marketing Experience The following additional adverse reactions have been reported during post-approval use of exenatide 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.

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6) and Drug Interactions (7) ]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . 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 &lt;30 mL/min) or end-stage renal disease and should be used with caution in patients with renal transplantation <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) ]</span> .

5.5 Severe Gastrointestinal Adverse Reactions Use of GLP-1 receptor agonists, including BYETTA, has been associated with gastrointestinal adverse reactions, sometimes severe <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6) and Drug Interactions (7) ]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . 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 &lt;30 mL/min) or end-stage renal disease and should be used with caution in patients with renal transplantation <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) ]</span> .

5.5 Severe Gastrointestinal Adverse Reactions Use of GLP-1 receptor agonists, including BYETTA, has been associated with gastrointestinal adverse reactions, sometimes severe <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

INTERACTIONS Table 6: Clinically Relevant Interactions with Exenatide 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 exenatide, 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, exenatide did not have a significant effect on INR [see Clinical Pharmacology (12.3) ] . There have been post-marketing 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 prothrombin time should be monitored more frequently after initiation or alteration of exenatide 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, exenatide 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 exenatide 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 exenatide injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when exenatide is not administered [see Clinical Pharmacology (12.3) ] . May impact absorption of orally administered medications. ( 7 ) Warfarin: Post-marketing reports of increased INR sometimes associated with bleeding. Monitor INR frequently until stable upon initiation or alteration of exenatide therapy. ( 7 )