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These highlights do not include all the information needed to use BYETTA safely and effectively. See full prescribing information for BYETTA. BYETTA (exenatide) Injection Initial U.S. Approval: 2005 | BYETTA [Physicians Total Care, Inc.] | BioPortfolio

12:32 EST 27th January 2019 | BioPortfolio

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BYETTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

BYETTA is not a substitute for insulin. BYETTA should not be used for the treatment of type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.

The concurrent use of BYETTA with prandial insulin has not been studied and cannot be recommended.

Based on postmarketing data BYETTA has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. BYETTA 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. Other antidiabetic therapies should be considered in patients with a history of pancreatitis.

BYETTA should be initiated at 5 mcg administered 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). BYETTA should not be administered after a meal. Based on clinical response, the dose of BYETTA can be increased to 10 mcg twice daily after 1 month of therapy. Initiation with 5 mcg reduces the incidence and severity of gastrointestinal side effects. Each dose should be administered as a subcutaneous (SC) injection in the thigh, abdomen, or upper arm. Do not mix BYETTA with insulin. Do not transfer BYETTA from the pen to a syringe or a vial. No data are available on the safety or efficacy of intravenous or intramuscular injection of BYETTA.

Use BYETTA only if it is clear, colorless and contains no particles.

BYETTA is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide in the following packages:

BYETTA is contraindicated in patients with prior severe hypersensitivity reactions to exenatide or to any of the product components.

Based on postmarketing data BYETTA has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYETTA, 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 should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, BYETTA should not be restarted. Consider antidiabetic therapies other than BYETTA in patients with a history of pancreatitis.

The risk of hypoglycemia is increased when BYETTA is used in combination with a sulfonylurea. Therefore, patients receiving BYETTA and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia.

When BYETTA is used in combination with insulin, the dose of insulin should be evaluated. In patients at increased risk of hypoglycemia consider reducing the dose of insulin [see Adverse Reactions (6.1)]. The concurrent use of BYETTA with prandial insulin has not been studied and cannot be recommended. It is also possible that the use of BYETTA with other glucose-independent insulin secretagogues (e.g. meglitinides) could increase the risk of hypoglycemia.

For additional information on glucose dependent effects see Mechanism of Action (12.1) .

BYETTA should not be used 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)]. In patients with end-stage renal disease receiving dialysis, single doses of BYETTA 5 mcg were not well-tolerated due to gastrointestinal side effects. Because BYETTA may induce nausea and vomiting with transient hypovolemia, treatment may worsen renal function. Caution should be applied when initiating or escalating doses of BYETTA from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min).

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 has not been found to be directly nephrotoxic in preclinical or clinical studies.

BYETTA has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Because BYETTA is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea, the use of BYETTA is not recommended in patients with severe gastrointestinal disease.

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 studies of BYETTA. In 3%, 4% 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)].

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 [see Adverse Reactions (6.2)].

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYETTA or any other antidiabetic drug.

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 TrialsA 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 blood glucose value consistent with hypoglycemia or prompt recovery after treatment for hypoglycemia.
BYETTA
Placebo twice daily 5 mcg twice daily 10 mcg twice daily
N = The number of Intent-to-Treat subjects in each treatment group.
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 (30 Weeks) When BYETTA was initiated in combination with insulin glargine, the dose of insulin glargine was decreased by 20% in patients with an HbA1c ≤ 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%

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) 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 [see Warnings and Precautions (5.5) ].

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 [see Warnings and Precautions (5.5) ].

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 [see Warnings and Precautions (5.5)].

Antibodies to exenatide were not assessed in the 30-week trial of BYETTA used in combination with insulin glargine.

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.

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.

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
%
BID = twice daily.
Nausea 0 8
Vomiting 0 4
Dyspepsia 0 3

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 [see Warnings and Precautions (5.2)] are summarized in Table 3.

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.

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
%
BID = twice daily.
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

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.

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.

Table 4: Treatment-Emergent Adverse Reactions ≥2% Incidence With BYETTA Used With a Thiazolidinedione, With or Without Metformin (Excluding Hypoglycemia)In a 16-week placebo-controlled clinical trial.
With a TZD or TZD/MET Placebo
N = 112
%
All BYETTA BID
N = 121
%
BID = twice daily.
Nausea 15 40
Vomiting 1 13
Dyspepsia 1 7
Diarrhea 3 6
Gastroesophageal Reflux Disease 0 3

Add-on to insulin glargine with or without metformin and/or thiazolidinedione

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.

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.

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
%
BID = twice daily.
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

The following additional adverse reactions have been reported during post-approval use of BYETTA. 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 [see Warnings and Precautions (5.6)].

Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding [see Drug Interactions (7.2)].

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 [see Limitations of Use (1.2) and Warnings and Precautions (5.1)].

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 [see Warnings and Precautions (5.3)].

Skin and Subcutaneous Tissue Disorders: alopecia

The effect of BYETTA to slow gastric emptying can reduce the extent and rate of absorption of orally administered drugs. BYETTA should be used with caution in patients receiving oral medications that have narrow therapeutic index or require rapid gastrointestinal absorption [see Adverse Reactions (6.2)]. 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)].

There are postmarketing reports of increased INR sometimes associated with bleeding, with concomitant use of warfarin and BYETTA [see Adverse Reactions (6.2)]. In a drug interaction study, BYETTA did not have a significant effect on INR [see Clinical Pharmacology (12.3)]. In patients taking warfarin, prothrombin time should be monitored more frequently after initiation or alteration of BYETTA therapy. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on warfarin.

Pregnancy Category C

There are no adequate and well-controlled studies of BYETTA use in pregnant women. In animal studies, exenatide caused cleft palate, irregular skeletal ossification and an increased number of neonatal deaths. BYETTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 had no adverse fetal effects. At the maximal dose, 760 mcg/kg/day, systemic exposures were up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC [see Nonclinical Toxicology (13.3)].

In developmental toxicity studies, pregnant animals received exenatide subcutaneously during organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Moreover, fetuses from pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 demonstrated reduced fetal and neonatal growth, cleft palate and skeletal effects at systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC [see Nonclinical Toxicology (13.3)].

Lactating mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), experienced an increased number of neonatal deaths. Deaths were 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 [see Nonclinical Toxicology (13.3)].

Pregnancy Registry

Amylin Pharmaceuticals, Inc. maintains a Pregnancy Registry to monitor pregnancy outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling 1-800-633-9081.

It is not known whether exenatide is excreted in human milk. However, exenatide is present at low concentrations (less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing) in the milk of lactating mice. Many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from exenatide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account these potential risks against the glycemic benefits to the lactating woman. Caution should be exercised when BYETTA is administered to a nursing woman.

Safety and effectiveness of BYETTA have not been established in pediatric patients.

Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see Clinical Pharmacology (12.3)]. BYETTA was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. No differences in safety or effectiveness were observed between these patients and younger patients. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function.

BYETTA is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 mL/min) and should be used with caution in patients with renal transplantation. No dosage adjustment of BYETTA is required in patients with mild renal impairment (creatinine clearance 50 to 80 mL/min). Caution should be applied when initiating or escalating doses of BYETTA from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min) [see Clinical Pharmacology (12.3)].

No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment. Because exenatide is cleared primarily by the kidney, hepatic dysfunction is not expected to affect blood concentrations of exenatide [see Clinical Pharmacology (12.3)].

In a clinical study of BYETTA, 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) is a synthetic peptide that was originally identified in the lizard Heloderma suspectum. 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 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 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.

BYETTA 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 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 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 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 compared with saline (p <0.001 for both).

Figure 1: Mean (+SEM) Insulin Secretion Rate During Infusion of BYETTA 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 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 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.

Postprandial Glucose

In patients with type 2 diabetes, BYETTA reduces postprandial plasma glucose concentrations (Figure 2).

Figure 2: Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 of BYETTA Treatment in Patients With Type 2 Diabetes Treated With Metformin, a Sulfonylurea, or Both (N = 54)

Fasting Glucose

In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, immediate insulin release followed injection of BYETTA. Plasma glucose concentrations were significantly reduced with BYETTA compared with placebo (Figure 3).

Figure 3: Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations Following a One-Time Injection of BYETTA or Placebo in Fasting Patients With Type 2 Diabetes (N = 12)

Cardiac Electrophysiology

The effect of exenatide 10 µg subcutaneously on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover thorough QTc study in 62 healthy subjects. In this study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms. Thus, BYETTA (10 mcg single dose) was not associated with clinically meaningful prolongation of the QTc interval.

Absorption

Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 h. The mean peak exenatide concentration (C) was 211 pg/mL and overall mean area under the time-concentration curve (AUC) was 1036 pg∙h/mL following SC administration of a 10-mcg dose of BYETTA. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 mcg to 10 mcg. The C values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of BYETTA in the abdomen, thigh, or upper arm.

Distribution

The mean apparent volume of distribution of exenatide following SC administration of a single dose of BYETTA is 28.3 L.

Metabolism and Elimination

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/h and the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 h post-dose.

Drug Interactions

Acetaminophen

When 1000 mg acetaminophen elixir was given with 10 mcg BYETTA (0 h) and 1 hour, 2 hours, and 4 hours after BYETTA injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; C was decreased by 37%, 56%, 54%, and 41%, respectively; T was increased from 0.6 hour in the control period to 0.9 hour, 4.2 hours, 3.3 hours, and 1.6 hours, respectively. Acetaminophen AUC, C and T were not significantly changed when acetaminophen was given 1 hour before BYETTA injection.

Digoxin

Administration of repeated doses of BYETTA (10 mcg BID) 30 minutes before oral digoxin (0.25 mg QD) decreased the C of digoxin by 17% and delayed the T of digoxin by approximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g., AUC) of digoxin was not changed.

Lovastatin

Administration of BYETTA (10 mcg BID) 30 minutes before a single oral dose of lovastatin (40 mg) decreased the AUC and Cof lovastatin by approximately 40% and 28%, respectively, and delayed the T by about 4 hours compared with lovastatin administered alone. In the 30-week controlled clinical trials of BYETTA, the use of BYETTA in patients already receiving HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles compared to baseline.

Lisinopril

In patients with mild to moderate hypertension stabilized on lisinopril (5 to 20 mg/day), BYETTA (10 mcg BID) did not alter steady-state C or AUC of lisinopril. Lisinopril steady-state T was delayed by 2 hours. There were no changes in 24-h mean systolic and diastolic blood pressure.

Oral Contraceptives

The effect of BYETTA (10 mcg BID) on single and on multiple doses of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied in healthy female subjects. Repeated daily doses of the oral contraceptive (OC) given 30 minutes after BYETTA administration decreased the C of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively and delayed the T of ethinyl estradiol and levonorgestrel by 3.0 hours and 3.5 hours, respectively, as compared to the oral contraceptive administered alone. Administration of repeated daily doses of the OC one hour prior to BYETTA administration decreased the mean C of ethinyl estradiol by 15% but the mean C of levonorgestrel was not significantly changed as compared to when the OC was given alone. BYETTA did not alter the mean trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens. However, the mean trough concentration of ethinyl estradiol was increased by 20% when the OC was administered 30 minutes after BYETTA administration injection as compared to when the OC was given alone. The effect of BYETTA on OC pharmacokinetics is confounded by the possible food effect on OC in this study. Therefore, OC products should be administered at least one hour prior to BYETTA injection.

Warfarin

Administration of warfarin (25 mg) 35 minutes after repeated doses of BYETTA (5 mcg BID on days 1-2 and 10 mcg BID on days 3-9) in healthy volunteers delayed warfarin T by approximately 2 hours. No clinically relevant effects on C or AUC of S- and R-enantiomers of warfarin were observed. BYETTA did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of warfarin [see Drug Interactions (7.2)].

Specific Populations

Renal Impairment

Pharmacokinetics of exenatide was studied in subjects with normal, mild, or moderate renal impairment and subjects with end stage renal disease. In subjects with mild to moderate renal impairment (creatinine clearance 30 to 80 mL/min), exenatide exposure was similar to that of subjects with normal renal function. However, in subjects with end-stage renal disease receiving dialysis, mean exenatide exposure increased by 3.37-fold compared to that of subjects with normal renal function. [see Use in Specific Populations (8.6)].

Hepatic Impairment

No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment [see Use in Specific Populations (8.7)].

Age

Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see Use in Specific Population (8.5)].

Gender

Population pharmacokinetic analysis of male and female patients suggests that gender does not influence the distribution and elimination of exenatide.

Race

Population pharmacokinetic analysis of samples from Caucasian, Hispanic, Asian, and Black patients suggests that race has no significant influence on the pharmacokinetics of exenatide.

Body Mass Index

Population pharmacokinetic analysis of patients with body mass indices (BMI) ≥30 kg/m and <30 kg/msuggests that BMI has no significant effect on the pharmacokinetics of exenatide.

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 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.

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 HbA ranging from 6.5-10%. 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 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 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in HbA from baseline at Week 24 (Table 6).

On average, there were no adverse effects of exenatide on blood pressure or lipids.

Table 6: Results of 24-Week Placebo-Controlled Trial of BYETTA Used as Monotherapy
Placebo
BID
BYETTA
5 mcg
BID
BYETTA
10 mcgBYETTA 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 5 months before the morning and evening meals.
BID
BID = twice daily.
Intent-to-Treat Population (N) 77 77 78
HbA1c (%), Mean
  Baseline 7.8 7.9 7.8
  Change at Week 24Least 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 HbA1c <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]

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 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 (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 Caucasian, 8% were Hispanic and 3% were Black. The mean baseline HbA values were 7.9% for BYETTA and placebo.

The primary endpoint in each study was the mean change in HbA from baseline to study end (or early discontinuation). Table 7 summarizes the study results for the 30-week and 16-week clinical trials.

Table 7: 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 BID
In Combination With Metformin (30 Weeks)
BID = twice daily.
Intent-to-Treat Population (N) 113 110 113
HbA1c (%), Mean
  Baseline 8.2 8.3 8.2
  Change at Week 30Least squares means are adjusted for baseline HbA1c 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 HbA1c <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 GlucoseMeasured 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
HbA1c (%), 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 HbA1c <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
HbA1c (%), 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 HbA1c <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
HbA1c (%), 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 HbA1c <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]

HbA

The addition of BYETTA to a regimen of metformin, a sulfonylurea, or both, resulted in statistically significant reductions from baseline in HbA compared with patients receiving placebo added to these agents in the three controlled trials (Table 7).

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 compared with patients receiving placebo (Table 7).

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-h 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).

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 HbA ≤8.0% decreased their prestudy dose of insulin glargine by 20% and patients with an HbA ≥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 Caucasian, 10% were American Indian or Alaska Native, 9% were Black, 3% were Asian, and 0.8% were of multiple origins.

The primary endpoint was the change in HbA from baseline to Week 30. Compared to placebo, BYETTA 10 mcg BID resulted in statistically significant reductions in HbA from baseline at Week 30 (Table 8) in patients receiving titrated insulin glargine.

Table 8: 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 mcgBYETTA 5 mcg twice daily for 1 month followed by 10 mcg BID for 5 months for the 30-week trial. BID + Titrated Insulin Glargine
BID = twice daily.
Intent-to-Treat Population (N) 122 137
HbA1c (%), Mean
  Baseline 8.5 8.3
  Change at Week 30Least squares means are based on a mixed model adjusting for treatment, pooled investigator, visit, baseline HbA1c 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 HbA1c <7% 30% 57%
Body Weight (kg), Mean
  Baseline 93.8 95.4
  Change at Week 30Least squares means are based on a mixed model adjusting for treatment, pooled investigator, visit, baseline HbA1c 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 (mg/dL), Mean
  Baseline 133 132
  Change at Week 30 -16 -23
  Difference from placebo (95% CI) -7 [-18, 3]
Table 9: Dosing Algorithm for Titration of Insulin GlargineAdapted from Riddle et al. 2003.
Fasting Plasma Glucose Values
(mg/dL)
Dose Change
(U)
Abbreviations: U = units.
<56Value for at least 1 fasting plasma glucose measurement since the last assessment. -4
56 to 72 -2
73 to 99Based 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

BYETTA 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 54868-5384-010 mcg per dose, 60 doses, 2.4 mL prefilled pen, NDC 54868-5384-1

Patients should be advised that BYETTA pens are never to be shared with another patient.

Patients should be informed of the potential risks and benefits of BYETTA and of alternative modes of therapy. Patients should also be fully informed about self-management practices, including the importance of proper storage of BYETTA, injection technique, timing of dosage of BYETTA 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 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 and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.1)].

The risk of hypoglycemia is increased when BYETTA is used in combination with a sulfonylurea. Therefore, patients receiving BYETTA and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia. Patients should be informed that it is also possible that the use of BYETTA with other glucose-independent insulin secretagogues (e.g., meglitinides) could increase the risk of hypoglycemia.

When BYETTA is used in combination with insulin, evaluate the dose of insulin. Consider reducing the dose of insulin in patients at increased risk of hypoglycemia [see Adverse Reactions (6.1)]. Patients treated with BYETTA should be informed that the concurrent use of BYETTA with prandial insulin has not been studied and cannot be recommended.

The symptoms, treatment, and conditions that predispose to development of hypoglycemia should be explained to the patient. The patient's usual instructions for hypoglycemia management should be reviewed and reinforced when initiating BYETTA therapy, particularly when concomitantly administered with a sulfonylurea or insulin [see Warnings and Precautions (5.2)].

Patients treated with BYETTA 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 [see Warnings and Precautions (5.3)].

Patients should be informed that serious hypersensitivity reactions have been reported during postmarketing use of BYETTA. If symptoms of hypersensitivity reactions occur, patients must stop taking BYETTA and seek medical advice promptly [see Warnings and Precautions (5.6)].

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

Each dose of BYETTA should be administered as a SC injection in the thigh, abdomen, or upper arm 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). BYETTA should not be administered after a meal. If a dose is missed, the treatment regimen should be resumed as prescribed with the next scheduled dose.

Patients should be advised that treatment with BYETTA 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 may also result in nausea, particularly upon initiation of therapy [see Adverse Reactions (6)].

The patient should read the Medication Guide and the Pen User Manual before starting BYETTA 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 921211-800-868-1190

http://www.BYETTA.com

This product and its use are covered by US Patent Nos. 5,424,286, 6,858,576, 6,872,700, 6,902,744, 6,956,026, 7,297,761, 7,521,423, 7,741,269, and other patents pending.

Literature Revised December 2011

BYETTA is a registered trademark of Amylin Pharmaceuticals, Inc.

© 2005, 2011 Amylin Pharmaceuticals, Inc. All rights reserved. 822017-AA

Additional barcode labeling by: Physicians Total Care, Inc.Tulsa, Oklahoma       74146

Medication Guide

BYETTA (bye-A-tuh) (exenatide) Injection

Read this Medication Guide and the Pen User Manual that come with BYETTA before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have questions about BYETTA after reading this information, ask your healthcare provider or pharmacist.

What is the most important information I should know about BYETTA?

Serious side effects can happen in people who take BYETTA, including inflammation of the pancreas (pancreatitis) which may be severe and lead to death.

Before taking BYETTA, tell your healthcare provider if you have had:

These medical conditions can make you more likely to get pancreatitis in general. It is not known if having these conditions will lead to a higher chance of getting pancreatitis while taking BYETTA.

While taking BYETTA:

Call your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe, and will not go away. The pain may happen with or without vomiting. The pain may be felt going from your abdomen through to your back. These may be symptoms of pancreatitis.

What is BYETTA?

Who should not use BYETTA?

Do not use BYETTA if:

Symptoms of a severe allergic reaction with BYETTA may include:

What should I tell my healthcare provider before using BYETTA?

Before taking BYETTA, tell your healthcare provider if you:

Tell your healthcare provider about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. BYETTA slows stomach emptying and can affect medicines that need to pass through the stomach quickly. BYETTA may affect the way some medicines work and some other medicines may affect the way BYETTA works.

Especially tell your healthcare provider if you take:

Ask your healthcare provider if you are not sure if your medicine is listed above.

Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist each time you get a new medicine.

How should I use BYETTA?

See the Pen User Manual that comes with BYETTA for instructions for using the BYETTA Pen and injecting BYETTA.

What are the possible side effects of BYETTA?

BYETTA can cause serious side effects.

See "What is the most important information I should know about BYETTA?"

It is not known whether BYETTA, or other anti-diabetes medications, increase your risk of a heart attack or stroke.

Talk with your healthcare provider about how to treat low blood sugar.

The most common side effects with BYETTA include:

Talk to your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the side effects with BYETTA.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store BYETTA?

General information about BYETTA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BYETTA for a condition for which it was not prescribed. Do not give BYETTA to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide includes the most important information you should know about using BYETTA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about BYETTA that is written for health professionals.

For more information about BYETTA, go to http://www.BYETTA.com or call BYETTA Customer Service at 1-800-868-1190.

What are the ingredients in BYETTA?

Active Ingredient: exenatide

Inactive Ingredients: metacresol, mannitol, glacial acetic acid, and sodium acetate trihydrate in water for injection.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised December 2011

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

BYETTA is a registered trademark of Amylin Pharmaceuticals, Inc.All other marks are the marks of their respective owners.

© 2005, 2011 Amylin Pharmaceuticals, Inc. All rights reserved. 823015-AA

swelling of your face, lips, tongue, or throat problems breathing or swallowing severe rash or itching fainting or feeling dizzy very rapid heartbeat

5 mcg PEN USER MANUAL

Section 1 Read this section completely before you begin. Then, move on to Section 2–Getting Started.

WHAT YOU NEED TO KNOW ABOUT YOUR BYETTA PEN

PEN USER MANUAL

Read these instructions carefully BEFORE using your BYETTA Pen. For complete dosing and safety information, also read the BYETTA Medication Guide that comes with the BYETTA Pen carton.

It is important that you use your pen correctly. Failure to follow these instructions completely may result in a wrong dose, a broken pen or an infection.

These instructions do not take the place of talking with your healthcare provider about your medical condition or your treatment. If you are having problems using your BYETTA Pen, call toll free 800-868-1190.

IMPORTANT INFORMATION ABOUT YOUR BYETTA PEN

ABOUT PEN NEEDLES

What kinds of needles can be used with my BYETTA Pen?

Do I use a new needle for each injection?

How do I throw away my needles?

Never share your BYETTA pen or needles with another person. You may give an infection to them, or get an infection from them, and BYETTA may harm them.

STORING YOUR BYETTA PEN

How do I store my BYETTA Pen?

Keep your pen and needles out of the reach of children.

How long can I use a BYETTA Pen?

Date of First Use                        Date to Throw Away Pen                  

How do I clean my BYETTA Pen?

See the complete BYETTA Medication Guide that comes with BYETTA. For more information,call toll free 800-868-1190 or visit www.BYETTA.com

Section 2 Read and follow the directions in this section only after you've read Section 1—What You Need To Know About Your BYETTA Pen.

GETTING STARTED

Set up your new pen just before you use it the first time. For routine use, do not repeat this one-time-only new pen setup. If you do, you will run out of BYETTA before 30 days of use.

Section 4

COMMONLY ASKED QUESTIONS

1. Do I need to do the One-Time-Only New Pen Setup before every dose?

2. Why are there air bubbles in the cartridge?

3. What should I do if BYETTA does not come out of the needle tip after four tries during One-Time-Only New Pen Setup?

4. Why do I see BYETTA leaking from my needle after I have finished my injection?

It is normal for a single drop to remain on the tip of your needle after your injection is complete. If you see more than one drop:

5. How can I tell when the injection is complete?

The injection is complete when:

If you hear a click sound from your BYETTA Pen, ignore it. You must follow all the steps listed above to make sure your injection is complete.

6. Where should I inject BYETTA?

Inject BYETTA into your abdomen, thigh, or upper arm using the injection method explained to you by your healthcare provider.

7. What if I cannot pull, turn, or push the dose knob?

Manufactured for Amylin Pharmaceuticals, Inc., San Diego, CA 92121. All rights reserved. BYETTA is a registered trademark of Amylin Pharmaceuticals, Inc.© 2007, 2011 Amylin Pharmaceuticals, Inc.Literature revised December 2011825001-08PV 5017 UCP

Byetta®
exenatide injection
 
250 mcg/mL, 1.2 mL
 
5 mcg

PEN USER MANUAL
ONE-TIME-ONLY NEW PEN SETUP
 
STEP A Check the Pen
Note: A small air bubble in the cartridge is normal.
Wash hands prior to use. Check pen label to make sure it is your 5 mcg pen. Pull off the blue pen cap. Check BYETTA in the cartridge. The liquid should be clear, colorless, and free of particles. If not, do not use.
 
STEP B Attach the Needle
Remove paper tab from outer needle shield. Push outer needle shield containing the needle straight onto the pen, then screw needle on until secure. Pull off outer needle shield. Do not throw away. Pull off inner needle shield and throw away. A small drop of liquid may appear. This is normal.
 
STEP C Dial the Dose
Check that the is in the dose window. If not, turn dose knob away from you (clockwise) until it stops and the is in the dose window. Pull dose knob out until it stops and the is in the dose window. Turn dose knob away from you until it stops at . Make sure that the 5 with the line under it is in the center of the dose window.
Note: If you cannot turn the dose knob away from you to the , see Commonly Asked Questions, number 7 , in Section 4 of this user manual.
 
STEP D Prepare the Pen
Point the needle of the pen up and away from you.         PUSH & HOLD Use thumb to firmly push injection button in until it stops, then continue holding the injection button in while slowly counting to 5. If you do not see a stream or several drops come from the needle tip, repeat Steps C & D. Pen preparation is complete when the is in the center of the dose window AND you have seen a stream or several drops come from the needle tip.
Note: If you do not see liquid after 4 times, see Commonly Asked Questions, number 3 , in Section 4 of this user manual.
 
STEP E Complete New Pen Setup
Turn dose knob away from you until it stops and the is in the dose window. For routine use, do not repeat this one-time-only new pen setup. If you do, you will run out of BYETTA before 30 days of use. You are now ready for your first dose of BYETTA. Go to Section 3, Step 3, for instructions on how to inject your first routine dose.
Note: If you cannot turn the dose knob, see Commonly Asked Questions, number 7 , in Section 4 of user manual.
Section 3
Now that you have done the one-time-only new pen setup, follow Section 3 for all of your injections.
 
ROUTINE USE
 
STEP 1 Check the Pen
Wash hands prior to use. Check pen label to make sure it is your 5 mcg pen. Pull off the blue pen cap. Check BYETTA in the cartridge. The liquid should be clear, colorless, and free of particles. If it is not, do not use. Note: A small air bubble will not harm you or affect your dose.
 
STEP 2 Attach the Needle
Remove paper tab from outer needle shield. Push outer needle shield containing the needle straight onto pen, then screw needle on until secure. Pull off outer needle shield. Do not throw away. Pull off inner needle shield and throw away. A small drop of liquid may appear. This is normal.
 
STEP 3 Dial the Dose
Check that the is in the dose window. If not, turn dose knob away from you (clockwise) until it stops and the is in the dose window. Pull dose knob out until it stops and the is in the dose window. Turn dose knob away from you until it stops at . Make sure that the 5 with the line under it is in the center of the dose window.
Note: If you cannot turn the dose knob away from you to the , see Commonly Asked Questions, number 7 , in Section 4 of this user manual.
 
STEP 4 Inject the Dose
Grip pen firmly. Insert needle into skin using the under-the-skin (subcutaneous) injection method explained by your healthcare provider.         PUSH & HOLD Use thumb to firmly push injection button in until it stops. Continue holding in the injection button while slowly counting to 5 to get a full dose. Remove needle from skin. Injection is complete when the is in the center of the dose window. The pen is now ready to reset.
Note: If you see several drops of BYETTA leaking from the needle after the injection, you may not have received a complete dose. See Commonly Asked Questions, number 4 , in Section 4 of this user manual.
 
STEP 5 Reset the Pen
Turn dose knob away from you until it stops and the is in the dose window. Note: If you cannot turn the dose knob, or if your pen leaks, your full dose has not been delivered. See Commonly Asked Questions, numbers 4 and 7 , in Section 4 of this user manual.
 
STEP 6 Remove and Dispose of the Needle
Carefully put the outer needle shield back over the needle. Remove the needle after each injection. Unscrew the needle. Throw away needles in a puncture-resistant container or as recommended by your healthcare provider.
 
STEP 7 Store Pen for Next Dose
See the complete BYETTA Medication Guide
that comes with BYETTA. For more information,
call toll free 800-868-1190 or visit www.BYETTA.com
Byetta®
exenatide injection

10 mcg PEN USER MANUAL

Section 1 Read this section completely before you begin. Then, move on to Section 2—Getting Started.

WHAT YOU NEED TO KNOW ABOUT YOUR BYETTA PEN

PEN USER MANUAL

Read these instructions carefully BEFORE using your BYETTA Pen. For complete dosing and safety information, also read the BYETTA Medication Guide that comes with the BYETTA Pen carton.

It is important that you use your pen correctly. Failure to follow these instructions completely may result in a wrong dose, a broken pen or an infection.

These instructions do not take the place of talking with your healthcare provider about your medical condition or your treatment. If you are having problems using your BYETTA Pen, call toll free 800-868-1190.

IMPORTANT INFORMATION ABOUT YOUR BYETTA PEN

ABOUT PEN NEEDLES

What kinds of needles can be used with my BYETTA Pen?

Do I use a new needle for each injection?

How do I throw away my needles?

Never share your BYETTA pen or needles with another person. You may give an infection to them, or get an infection from them, and BYETTA may harm them.

STORING YOUR BYETTA PEN

How do I store my BYETTA Pen?

Keep your pen and needles out of the reach of children.

How long can I use a BYETTA Pen?

Date of First Use                        Date to Throw Away Pen                  

How do I clean my BYETTA Pen?

See the complete BYETTA Medication Guide that comes with BYETTA. For more information,call toll free 800-868-1190 or visit www.BYETTA.com

Section 2 Read and follow the directions in this section only after you've read Section 1—What You Need To Know About Your BYETTA Pen.

GETTING STARTED

Set up your new pen just before you use it the first time. For routine use, do not repeat this one-time-only new pen setup. If you do, you will run out of BYETTA before 30 days of use.

Section 4

COMMONLY ASKED QUESTIONS

1. Do I need to do the One-Time-Only New Pen Setup before every dose?

2. Why are there air bubbles in the cartridge?

3. What should I do if BYETTA does not come out of the needle tip after four tries during One-Time-Only New Pen Setup?

4. Why do I see BYETTA leaking from my needle after I have finished my injection?

It is normal for a single drop to remain on the tip of your needle after your injection is complete. If you see more than one drop:

5. How can I tell when the injection is complete?

The injection is complete when:

If you hear a click sound from your BYETTA Pen, ignore it. You must follow all the steps listed above to make sure your injection is complete.

6. Where should I inject BYETTA?

Inject BYETTA into your abdomen, thigh, or upper arm using the injection method explained to you by your healthcare provider.

7. What if I cannot pull, turn, or push the dose knob?

Manufactured for Amylin Pharmaceuticals, Inc., San Diego, CA 92121. All rights reserved. BYETTA is a registered trademark of Amylin Pharmaceuticals, Inc.© 2007, 2011 Amylin Pharmaceuticals, Inc.Literature revised December 2011925001-08PV 5027 UCP

Byetta®
exenatide injection
 
250 mcg/mL, 2.4 mL
 
10 mcg

PEN USER MANUAL
ONE-TIME-ONLY NEW PEN SETUP
 
STEP A Check the Pen
Note: A small air bubble in the cartridge is normal.
Wash hands prior to use. Check pen label to make sure it is your 10 mcg pen. Pull off the blue pen cap. Check BYETTA in the cartridge. The liquid should be clear, colorless, and free of particles. If not, do not use.
 
STEP B Attach the Needle
Remove paper tab from outer needle shield. Push outer needle shield containing the needle straight onto the pen, then screw needle on until secure. Pull off outer needle shield. Do not throw away. Pull off inner needle shield and throw away. A small drop of liquid may appear. This is normal.
 
STEP C Dial the Dose
Check that the is in the dose window. If not, turn dose knob away from you (clockwise) until it stops and the is in the dose window. Pull dose knob out until it stops and the is in the dose window. Turn dose knob away from you until it stops at . Make sure that the 10 with the line under it is in the center of the dose window.
Note: If you cannot turn the dose knob away from you to the , see Commonly Asked Questions, number 7 , in Section 4 of this user manual.
 
STEP D Prepare the Pen
Point the needle of the pen up and away from you.         PUSH & HOLD Use thumb to firmly push injection button in until it stops, then continue holding the injection button in while slowly counting to 5. If you do not see a stream or several drops come from the needle tip, repeat Steps C & D. Pen preparation is complete when the is in the center of the dose window AND you have seen a stream or several drops come from the needle tip.
Note: If you do not see liquid after 4 times, see Commonly Asked Questions, number 3 , in Section 4 of this user manual.
 
STEP E Complete New Pen Setup
Turn dose knob away from you until it stops and the is in the dose window. For routine use, do not repeat this one-time-only new pen setup. If you do, you will run out of BYETTA before 30 days of use. You are now ready for your first dose of BYETTA. Go to Section 3, Step 3, for instructions on how to inject your first routine dose.
Note: If you cannot turn the dose knob, see Commonly Asked Questions, number 7 , in Section 4 of user manual.
Section 3
Now that you have done the one-time-only new pen setup, follow Section 3 for all of your injections.
 
ROUTINE USE
 
STEP 1 Check the Pen
Wash hands prior to use. Check pen label to make sure it is your 10 mcg pen. Pull off the blue pen cap. Check BYETTA in the cartridge. The liquid should be clear, colorless, and free of particles. If it is not, do not use. Note: A small air bubble will not harm you or affect your dose.
 
STEP 2 Attach the Needle
Remove paper tab from outer needle shield. Push outer needle shield containing the needle straight onto pen, then screw needle on until secure. Pull off outer needle shield. Do not throw away. Pull off inner needle shield and throw away. A small drop of liquid may appear. This is normal.
 
STEP 3 Dial the Dose
Check that the is in the dose window. If not, turn dose knob away from you (clockwise) until it stops and the is in the dose window. Pull dose knob out until it stops and the is in the dose window. Turn dose knob away from you until it stops at . Make sure that the 10 with the line under it is in the center of the dose window.
Note: If you cannot turn the dose knob away from you to the , see Commonly Asked Questions, number 7 , in Section 4 of this user manual.
 
STEP 4 Inject the Dose
Grip pen firmly. Insert needle into skin using the under-the-skin (subcutaneous) injection method explained by your healthcare provider.         PUSH & HOLD Use thumb to firmly push injection button in until it stops. Continue holding in the injection button while slowly counting to 5 to get a full dose. Remove needle from skin. Injection is complete when the is in the center of the dose window. The pen is now ready to reset.
Note: If you see several drops of BYETTA leaking from the needle after the injection, you may not have received a complete dose. See Commonly Asked Questions, number 4 , in Section 4 of this user manual.
 
STEP 5 Reset the Pen
Turn dose knob away from you until it stops and the is in the dose window. Note: If you cannot turn the dose knob, or if your pen leaks, your full dose has not been delivered. See Commonly Asked Questions, numbers 4 and 7 , in Section 4 of this user manual.
 
STEP 6 Remove and Dispose of the Needle
Carefully put the outer needle shield back over the needle. Remove the needle after each injection. Unscrew the needle. Throw away needles in a puncture-resistant container or as recommended by your healthcare provider.
 
STEP 7 Store Pen for Next Dose
See the complete BYETTA Medication Guide
that comes with BYETTA. For more information,
call toll free 800-868-1190 or visit www.BYETTA.com
Byetta®
exenatide injection

PRINCIPAL DISPLAY PANEL - 5 mcg

5mcg

NDC 54868-5384-0

Byetta exenatide injection250 mcg/mL, 1.2 mL

Dispense the enclosed Medication Guide to each patient

Each prefilled pen will deliver 60 subcutaneous doses, 5 mcg per doseRx Only

SUBCUTANEOUS USE ONLY     REFRIGERATE – DO NOT FREEZEDO NOT TRANSFER THIS MEDICATION TO A SYRINGE

Pen needles not included

Ask your healthcare provider which pen needle length and gauge is best for youUse 29 (thin), 30, or 31 (thinner) gauge disposable pen needles

Manufacturer

Physicians Total Care, Inc.

Active Ingredients

Source

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