Byetta (Exenatide synthetic) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Byetta (Exenatide synthetic) is not a substitute for insulin. Byetta (Exenatide synthetic) should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

The concurrent use of Byetta (Exenatide synthetic) with insulin has not been studied and cannot be recommended.

Based on postmarketing data Byetta (Exenatide synthetic) has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Byetta (Exenatide synthetic) has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Byetta (Exenatide synthetic) . Other antidiabetic therapies should be considered in patients with a history of pancreatitis.

Byetta (Exenatide synthetic) is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide in the following packages:

Based on postmarketing data Byetta (Exenatide synthetic) has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of Byetta (Exenatide synthetic) , and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, Byetta (Exenatide synthetic) should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Byetta (Exenatide synthetic) should not be restarted. Consider antidiabetic therapies other than Byetta (Exenatide synthetic) in patients with a history of pancreatitis.
The risk of hypoglycemia is increased when Byetta (Exenatide synthetic) is used in combination with a sulfonylurea (hypoglycemia can also occur when other antidiabetic agents are used in combination with a sulfonylurea). Therefore, patients receiving Byetta (Exenatide synthetic) and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia. It is also possible that the use of Byetta (Exenatide synthetic) with other glucose-independent insulin secretagogues (e.g. meglitinides) could increase the risk of hypoglycemia.

For additional information on glucose dependent effects see .

Byetta (Exenatide synthetic) should not be used in patients with severe renal impairment (creatinine clearance There have been postmarketing reports of altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring hemodialysis or kidney transplantation. Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or hydration status, such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or diuretics. Some events occurred in patients who had been experiencing nausea, vomiting, or diarrhea, with or without dehydration. Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including Byetta (Exenatide synthetic) . Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Byetta (Exenatide synthetic) or any other antidiabetic drug.

The following additional adverse reactions have been reported during post-approval use of Byetta (Exenatide synthetic) . 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.

Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, macular or papular rash, angioedema, anaphylactic reaction .

Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding .

Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death .

Neurologic: dysgeusia; somnolence

Renal and Urinary Disorders: 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 Disorders: alopecia

In a clinical study of Byetta (Exenatide synthetic) , three patients with type 2 diabetes each experienced a single overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations. One of the three patients experienced severe hypoglycemia requiring parenteral glucose administration. The three patients recovered without complication. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

Byetta (Exenatide synthetic) (exenatide) is a synthetic peptide that was originally identified in the lizard Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), biguanides, thiazolidinediones, alpha-glucosidase inhibitors, amylinomimetics and dipeptidyl peptidase-4 inhibitors.

Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula CHNOS 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

Byetta (Exenatide synthetic) is supplied for SC injection 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, 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 or 10 mcg. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID).

Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. Byetta (Exenatide synthetic) is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.

The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide promotes insulin release from pancreatic beta cells in the presence of elevated glucose concentrations.

Byetta (Exenatide synthetic) improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.

Glucose-dependent insulin secretion: Byetta (Exenatide synthetic) has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. However, Byetta (Exenatide synthetic) does not impair the normal glucagon response to hypoglycemia.

First-phase insulin response: In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of Byetta (Exenatide synthetic) at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with Byetta (Exenatide synthetic) compared with saline (p
Figure 1: Mean (+SEM) Insulin Secretion Rate During Infusion of Byetta (Exenatide synthetic) or Saline in Patients With Type 2 Diabetes and During Infusion of Saline in Healthy Subjects
Glucagon secretion: In patients with type 2 diabetes, Byetta (Exenatide synthetic) moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand.

Gastric emptying: Byetta (Exenatide synthetic) slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.

Food intake: In both animals and humans, administration of exenatide has been shown to reduce food intake.

A 104-week carcinogenicity study was conducted in male and female rats at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection. Benign thyroid C-cell adenomas were observed in female rats at all exenatide doses. The incidences in female rats were 8% and 5% in the two control groups and 14%, 11%, and 23% in the low-, medium-, and high-dose groups with systemic exposures of 5, 22, and 130 times, respectively, the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on plasma area under the curve (AUC).

In a 104-week carcinogenicity study in mice at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 95 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay.

In mouse fertility studies with SC doses of 6, 68 or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating, and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7, there were no adverse fetal effects at doses up to 760 mcg/kg/day, systemic exposures up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 (organogenesis), cleft palate (some with holes) and irregular fetal skeletal ossification of rib and skull bones were observed at 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 (organogenesis), irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a systemic exposure 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In pregnant mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths was observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

Byetta (Exenatide synthetic) has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione.

In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, Byetta (Exenatide synthetic) 5 mcg BID (n = 77), Byetta (Exenatide synthetic) 10 mcg BID (n = 78), or placebo BID (n = 77) was used as monotherapy in patients with entry HbA ranging from 6.5-10%. All patients assigned to Byetta (Exenatide synthetic) initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive Byetta (Exenatide synthetic) 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. Byetta (Exenatide synthetic) or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were Caucasian, 26% were West Asian, 3% were Hispanic, 3% were Black, and 0.4% were East Asian.
The primary endpoint was the change in HbA from baseline to Week 24 (or the last value at time of early discontinuation). Compared to placebo, Byetta (Exenatide synthetic) 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in HbA from baseline at Week 24 (Table 5).
On average, there were no adverse effects of exenatide on blood pressure or lipids.

Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of Byetta (Exenatide synthetic) 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 (Exenatide synthetic) 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 (Exenatide synthetic) 5 mcg BID, Byetta (Exenatide synthetic) 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 (Exenatide synthetic) initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive Byetta (Exenatide synthetic) 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 Caucasian, 224 (16%) were Hispanic, and 174 (12%) were Black. Mean HbA values at baseline for the trials ranged from 8.2% to 8.7%.

In the placebo-controlled trial of 16 weeks duration, Byetta (Exenatide synthetic) (n = 121) or placebo (n = 112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin. Randomization to Byetta (Exenatide synthetic) or placebo was stratified based on whether the patients were receiving metformin. Byetta (Exenatide synthetic) 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 (Exenatide synthetic) 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 Caucasian, 8% were Hispanic and 3% were Black. The mean baseline HbA values were 7.9% for Byetta (Exenatide synthetic) and placebo.

The primary endpoint in each study was the mean change in HbA from baseline to study end (or early discontinuation). Table 6 summarizes the study results for the 30-week and 16-week clinical trials.

Byetta (Exenatide synthetic) is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide.

The following packages are available: 5 mcg per dose, 60 doses, 1.2 mL prefilled pen, NDC 54868-5384-0 10 mcg per dose, 60 doses, 2.4 mL prefilled pen, NDC 54868-5384-1

Patients should be informed of the potential risks and benefits of Byetta (Exenatide synthetic) and of alternative modes of therapy. Patients should also be fully informed about self-management practices, including the importance of proper storage of Byetta (Exenatide synthetic) , injection technique, timing of dosage of Byetta (Exenatide synthetic) and concomitant oral drugs, adherence to meal planning, regular physical activity, periodic blood glucose monitoring and HbA testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications.

Patients should be advised to inform their physicians if they are pregnant or intend to become pregnant.

Each dose of Byetta (Exenatide synthetic) should be administered as a SC injection in the thigh, abdomen, or upper arm at any time within the 60-minute period the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Byetta (Exenatide synthetic) be administered after a meal. If a dose is missed, the treatment regimen should be resumed as prescribed with the next scheduled dose.

The risk of hypoglycemia is increased when Byetta (Exenatide synthetic) is used in combination with an agent that induces hypoglycemia, such as a sulfonylurea. The symptoms, treatment, and conditions that predispose to development of hypoglycemia should be explained to the patient. While the patient's usual instructions for hypoglycemia management do not need to be changed, these instructions should be reviewed and reinforced when initiating Byetta (Exenatide synthetic) therapy, particularly when concomitantly administered with a sulfonylurea .

Patients should be advised that treatment with Byetta (Exenatide synthetic) may result in a reduction in appetite, food intake, and/or body weight, and that there is no need to modify the dosing regimen due to such effects. Treatment with Byetta (Exenatide synthetic) may also result in nausea, particularly upon initiation of therapy .

Patients should be informed that persistent severe abdominal pain that may radiate to the back and which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue Byetta (Exenatide synthetic) and contact their physician if persistent severe abdominal pain occurs .

Patients treated with Byetta (Exenatide synthetic) should be informed of the potential risk for worsening renal function and informed about associated signs and symptoms of renal dysfunction, as well as the possibility of dialysis as a medical intervention if renal failure occurs .

Patients should be informed that serious hypersensitivity reactions have been reported during postmarketing use of Byetta (Exenatide synthetic) . If symptoms of hypersensitivity reactions occur, patients must stop taking Byetta (Exenatide synthetic) and seek medical advice promptly .

The patient should read the Medication Guide and the Pen User Manual before starting Byetta (Exenatide synthetic) therapy and review them each time the prescription is refilled. The patient should be instructed on proper use and storage of the pen, emphasizing how and when to set up a new pen and noting that only one setup step is necessary at initial use. The patient should be advised not to share the pen and needles.

Patients should be informed that pen needles are not included with the pen and must be purchased separately. Patients should be advised which needle length and gauge should be used.

Manufactured for Amylin Pharmaceuticals, Inc., San Diego, CA 92121

Marketed by Amylin Pharmaceuticals, Inc. and Eli Lilly and Company1-800-868-1190

http://www.Byetta (Exenatide synthetic) .com

Literature Revised September 2010

Byetta (Exenatide synthetic) is a registered trademark of Amylin Pharmaceuticals, Inc.

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