Brand Name
Byetta
Generic Name
Exenatide
View Brand Information FDA approval date: December 10, 2014
Classification: GLP-1 Receptor Agonist
Form: Injection
What is Byetta (Exenatide)?
Exenatide injection is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Exenatide injection is a glucagon-like peptide-1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Co-administration with other exenatide-containing products is not recommended. Limitations of Use Exenatide injection contains exenatide. Co-administration with other exenatide-containing products is not recommended.
Approved To Treat
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Brand Information
Byetta (exenatide)
1INDICATIONS AND USAGE
BYETTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Limitations of Use
- BYETTA contains exenatide. Coadministration with other exenatide-containing products is not recommended.
2DOSAGE FORMS AND STRENGTHS
BYETTA injection is a clear, colorless solution of exenatide supplied as follows:
- 5 mcg per dose in a single-patient-use prefilled pen containing 300 mcg/1.2 mL (250 mcg/mL), 60 doses.
- 10 mcg per dose in a single-patient-use prefilled pen containing 600 mcg/2.4 mL (250 mcg/mL), 60 doses.
3CONTRAINDICATIONS
BYETTA is contraindicated in patients with:
- A prior severe hypersensitivity reaction to exenatide or to any of the excipients in BYETTA. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with BYETTA
- A history of drug-induced immune-mediated thrombocytopenia from exenatide products. Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported with exenatide use
4ADVERSE REACTIONS
The following serious adverse reactions are described below or elsewhere in the prescribing information:
- Acute Pancreatitis
- Never Share a BYETTA Pen Between Patients
- Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
- Acute Kidney Injury Due to Volume Depletion
- Severe Gastrointestinal Adverse Reactions
- Immunogenicity
- Hypersensitivity
- Drug-Induced Thrombocytopenia
- Acute Gallbladder Disease
- Pulmonary Aspiration During General Anesthesia or Deep Sedation
4.1Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Hypoglycemia
Table 1 summarizes the incidence and rate of hypoglycemia with BYETTA in six placebo-controlled clinical trials.
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 the 16-week trial of BYETTA add-on to thiazolidinediones, with or without metformin, 36 patients (31%) had low titer antibodies to exenatide at 16 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 69 patients (60%) without antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks. Of these patients, 4 (4% overall) had an attenuated glycemic response to BYETTA; the remaining 6 (5% overall) had a glycemic response comparable to that of patients without antibodies.
In the 24-week trial of BYETTA used as monotherapy, 40 patients (28%) had low titer antibodies to exenatide at 24 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 101 patients (70%) without antibody titers. An additional 3 patients (2%) had higher titer antibodies at 24 weeks. Of these patients, 1 (1% overall) had an attenuated glycemic response to BYETTA; the remaining 2 (1% overall) had a glycemic response comparable to that of patients without antibodies.
Antibodies to exenatide were not assessed in the 30-week placebo-controlled trial of BYETTA used in combination with insulin glargine.
In the 30-week comparator-controlled trial of BYETTA used in combination with insulin glargine and metformin, 60 patients (20%) had low titer antibodies to exenatide at 30 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 234 patients (77%) without antibody titers. An additional 10 patients (3%) had higher titer antibodies at 30 weeks. Of these patients, 2 (1% overall) had an attenuated glycemic response to BYETTA; the remaining 8 (3% overall) had a glycemic response comparable to that of patients without antibodies.
Two hundred and ten patients with antibodies to exenatide in the BYETTA clinical trials were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. No treatment-emergent cross-reactive antibodies were observed across the range of titers.
Other Adverse Reactions
Monotherapy
For the 24-week placebo-controlled study of BYETTA used as a monotherapy, Table 2 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients.
Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite, diarrhea, and dizziness. The most frequently reported adverse reaction associated with BYETTA, nausea, occurred in a dose-dependent fashion.
Two of the 155 patients treated with BYETTA withdrew due to adverse reactions of headache and nausea. No placebo-treated patients withdrew due to adverse reactions.
Cholelithiasis and cholecystitis
In a clinical study with exenatide, 1.9% of exenatide-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis.
Combination Therapy
Add-On to Metformin and/or Sulfonylurea
In the three 30-week controlled trials of BYETTA add-on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients are summarized in Table 3.
Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite. Nausea was the most frequently reported adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced nausea. Patients in the long-term uncontrolled open-label extension studies at 52 weeks reported no new types of adverse reactions than those observed in the 30-week controlled trials.
The most common adverse reactions leading to withdrawal for BYETTA-treated patients were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew due to nausea and none due to vomiting.
Add-On to Thiazolidinedione with or without Metformin
For the 16-week placebo-controlled study of BYETTA add-on to a thiazolidinedione, with or without metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with an incidence of ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients.
Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite. Chills (n=4) and injection-site reactions (n=2) occurred only in BYETTA-treated patients. The two patients who reported an injection-site reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic hypersensitivity pneumonitis) were reported in the BYETTA arm. No serious adverse events were reported in the placebo arm.
The most common adverse reactions leading to withdrawal for BYETTA-treated patients were nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to nausea.
Add-On to Insulin Glargine with or without Metformin and/or Thiazolidinedione (Placebo-Controlled)
For the 30-week placebo-controlled study of BYETTA as add-on to insulin glargine with or without oral antihyperglycemic medications, Table 5 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients.
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.
4.2Postmarketing Experience
The following additional adverse reactions have been reported during post approval use of BYETTA or other formulations of exenatide. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood: Drug induced thrombocytopenia.
Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding [see .
Gastrointestinal: Nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, ileus, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death
Hepatobiliary: Cholecystitis, cholelithiasis requiring cholecystectomy.
Hypersensitivity: Injection-site reactions, generalized pruritus and/or urticaria, macular or papular rash, angioedema, anaphylactic reaction.
Neurologic: Dysgeusia, somnolence, dysesthesia.
Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation.
Renal: Altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant, and kidney transplant dysfunction.
Skin and Subcutaneous Tissue: Alopecia.
5OVERDOSAGE
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, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Initiate appropriate supportive treatment according to the patient's clinical signs and symptoms.
6DESCRIPTION
BYETTA (exenatide) is a synthetic peptide, GLP-1 receptor agonist, that was originally identified in the lizard
Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula C
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 injection is supplied for subcutaneous administration as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg per dose or 10 mcg per dose. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID). Each prefilled device is filled with volume to allow delivery of 1.2 mL or 2.4 mL. Each device contains additional volume to allow for troubleshooting the device 4 times.
7CLINICAL STUDIES
BYETTA has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, a combination of metformin and a thiazolidinedione, or in combination with insulin glargine with or without metformin and/or thiazolidinedione.
7.1Monotherapy
In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, BYETTA 5 mcg BID (n=77), BYETTA 10 mcg BID (n=78), or placebo BID (n=77) was used as monotherapy in patients with entry HbA1c ranging from 6.5% to 10%. All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. BYETTA or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were White, 26% were West Asian, 3% were Hispanic or Latino ethnicity, 3% were Black or African American, and 0.4% were of East Asian ethnicity.
The primary endpoint was the change in HbA
On average, there were no adverse effects of exenatide on blood pressure or lipids.
7.2Combination Therapy with Oral Antihyperglycemic Medicines
Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of BYETTA in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea. In addition, a 16-week, placebo-controlled trial was conducted where BYETTA was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control.
In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned to receive BYETTA 5 mcg BID, BYETTA 10 mcg BID, or placebo BID before the morning and evening meals, in addition to their existing oral antidiabetic agent. All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the study. A total of 1446 patients were randomized in the three 30-week trials: 991 (69%) were White, 224 (16%) were Hispanic or Latino and 174 (12%) were of Black of African American ethnicity. Mean HbA1c values at baseline for the trials ranged from 8.2% to 8.7%.
In the placebo-controlled trial of 16 weeks duration, BYETTA (n=121) or placebo (n=112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin. Randomization to BYETTA or placebo was stratified based on whether the patients were receiving metformin. BYETTA treatment was initiated at a dose of 5 mcg BID for 4 weeks then increased to 10 mcg BID for 12 more weeks. Patients assigned to placebo received placebo BID throughout the study. BYETTA or placebo was injected subcutaneously before the morning and evening meals. In this trial, 79% of patients were taking a thiazolidinedione and metformin and 21% were taking a thiazolidinedione alone. The majority of patients (84%) were White, 8% were Hispanic or Latino ethnicity, and 3% were of Black or African American ethnicity. The mean baseline HbA1c values were 7.9% for BYETTA and placebo.
The primary endpoint in each study was the mean change in HbA
7.2.1HbAc
The addition of BYETTA to a regimen of metformin, a sulfonylurea, or both, resulted in statistically significant reductions from baseline in HbA
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
7.2.2Postprandial Glucose
Postprandial glucose was measured after a mixed meal tolerance test in 9.5% of patients participating in the 30-week add-on to metformin, add-on to sulfonylurea, and add-on to metformin in combination with sulfonylurea clinical trials. In this pooled subset of patients, BYETTA reduced postprandial plasma glucose concentrations in a dose-dependent manner. The mean (SD) change in 2-hour postprandial glucose concentration following administration of BYETTA at Week 30 relative to baseline was
8PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Acute Pancreatitis
Inform patients of the potential risk for acute pancreatitis and its symptoms: severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting. Instruct patients to discontinue BYETTA promptly and contact their physician if pancreatitis is suspected
Never Share a BYETTA Pen Between Patients
Advise patients that they must never share a BYETTA pen with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens
Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
Inform patients that the risk of hypoglycemia is increased when BYETTA is used in combination with an agent that induces hypoglycemia, such as a sulfonylurea or insulin. Educate patients on the signs and symptoms of hypoglycemia
Acute Kidney Injury Due to Volume Depletion
Inform patients of the potential risk of acute kidney injury due to dehydration associated with gastrointestinal adverse reactions. Advise patients to take precautions to avoid fluid depletion. Inform patients of the signs and symptoms of acute kidney injury and instruct them to promptly report any of these signs or symptoms or persistent (or extended) nausea, vomiting, and diarrhea to their healthcare provider
Severe Gastrointestinal Adverse Reactions
Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms
Drug-Induced Thrombocytopenia
Inform patients that drug-induced immune mediated thrombocytopenia has been reported during use of exenatide. Inform patients that if symptoms of thrombocytopenia occur, stop taking BYETTA and seek medical advice promptly
Hypersensitivity Reactions
Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of BYETTA. If symptoms of hypersensitivity reactions occur, instruct patients to stop taking BYETTA and seek medical advice promptly
Acute Gallbladder Disease
Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up
Pulmonary Aspiration During General Anesthesia or Deep Sedation
Inform patients that BYETTA may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking BYETTA
Pregnancy
Advise patients to inform their physicians if they are pregnant or intend to become pregnant.
Instructions
Instruct patients to administer BYETTA as a subcutaneous 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). Do not administer BYETTA after a meal. If a dose is missed, resume the treatment regimen as prescribed with the next scheduled dose.
Distributed by:
BYETTA
9Package/Label Display Panel – 5 mcg
5 mcg per dose
NDC 0310-6512-01
Byetta
250 mcg/mL, 1.2 mL
Dispense the enclosed Medication Guide to each patient
For Single Patient Use Only
Each prefilled pen will deliver 60 subcutaneous doses, 5 mcg per dose
Rx only
SUBCUTANEOUS USE ONLY
REFRIGERATE – DO NOT FREEZE
REFRIGERATE – DO NOT FREEZE
DO NOT TRANSFER THIS MEDICATION TO A SYRINGE
Pen needles not included
Ask your healthcare provider which pen needle length and gauge is best for you
AstraZeneca
10Package/Label Display Panel – 10 mcg
10 mcg per dose
NDC 0310-6524-01
Byetta
250 mcg/mL, 2.4 mL
Dispense the enclosed Medication Guide to each patient
For Single Patient Use Only
Each prefilled pen will deliver 60 subcutaneous doses, 10 mcg per dose
Rx only
SUBCUTANEOUS USE ONLY
REFRIGERATE – DO NOT FREEZE
REFRIGERATE – DO NOT FREEZE
DO NOT TRANSFER THIS MEDICATION TO A SYRINGE
Pen needles not included
Ask your healthcare provider which pen needle length and gauge is best for you
AstraZeneca
