EXENATIDE

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.

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.

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 exenatide injection 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 exenatide injection 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 exenatide injection if the solution appears clear, colorless and contains no particles. When using exenatide injection with insulin, administer as separate injections and never mix. It is acceptable to inject exenatide injection 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 )

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.

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 )