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. BYETTA (exenatide) is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 , 14 ) Limitations of Use
Coadministration with other exenatide-containing products is not recommended ( 1 ).
Contraindications
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 [see Warnings and Precautions (5.7) ].
A history of drug-induced immune-mediated thrombocytopenia from exenatide products. Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported with exenatide use [see Warnings and Precautions (5.8) ] .
History of severe hypersensitivity to exenatide or any of the excipients in BYETTA. (4)
History of drug-induced immune-mediated thrombocytopenia from exenatide products. ( 4 )
Warnings and precautions
Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including BYETTA. Discontinue if pancreatitis is suspected. ( 5.1 )
Never share a BYETTA pen between patients, even if the needle is changed. ( 5.2 )
Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: Patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. Reduction in the dose of insulin secretagogues or insulin may be necessary. ( 5.3 )
Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion ( 5.4 )
Severe Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe. BYETTA is not recommended in patients with severe gastroparesis. ( 5.5 )
Immunogenicity: Patients may develop antibodies to exenatide. If there is worsening glycemic control or failure to achieve target glycemic control, consider alternative antidiabetic therapy. ( 5.6 )
Hypersensitivity: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue BYETTA and promptly seek medical advice. ( 5.7 )
Drug-induced Immune-mediated Thrombocytopenia: Serious bleeding which may be fatal has been reported. Discontinue BYETTA promptly and avoid re-exposure to exenatide. ( 5.8 )
Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.9 )
Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.10 )
5.1Acute Pancreatitis
Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with glucagon-like peptide-1 (GLP-1) receptor agonists, including BYETTA [see Adverse Reactions (6.2) ] . After initiation of BYETTA, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting).
If pancreatitis is suspected, discontinue BYETTA and initiate appropriate management.
5.2Never Share a
BYETTA Pen Between Patients BYETTA pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.
5.3Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
Patients receiving BYETTA in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia including severe hypoglycemia [see Adverse Reactions (6) and Drug Interactions (7) ] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.
5.4Acute Kidney Injury Due to Volume Depletion
There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists, BYETTA [see Adverse Reactions (6.2) ] . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions (6) ] . Monitor renal function in patients reporting adverse reactions to BYETTA that could lead to volume depletion, especially during dosage initiation and escalation of BYETTA.
BYETTA is not recommended in patients with severe renal impairment (creatinine clearance <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) ] .
5.5 Severe Gastrointestinal Adverse Reactions Use of GLP-1 receptor agonists, including BYETTA, has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6) ] . BYETTA is not recommended in patients with severe gastroparesis.
5.6Immunogenicity
Patients may develop antibodies to exenatide following treatment with BYETTA. Antibody levels were measured in 90% of subjects in the 30-week, 24-week, and 16-week placebo-controlled studies and the 30-week comparator-controlled study of BYETTA. In 3%, 4%, 1%, and 1% of these patients, respectively, antibody formation was associated with an attenuated glycemic response. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered [see Adverse Reactions (6.1) ] .
5.7Hypersensitivity
There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) in patients treated with BYETTA. If a hypersensitivity reaction occurs, the patient should discontinue BYETTA and other suspect medications and promptly seek medical advice. Inform and closely monitor patients with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist for allergic reactions, because it is unknown whether such patients will be predisposed to anaphylaxis with BYETTA [see Adverse Reactions (6.2) ] .
5.8Drug-Induced Thrombocytopenia
Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported in the postmarketing setting with exenatide use. Drug-induced thrombocytopenia is an immune-mediated reaction, with exenatide-dependent anti-platelet antibodies. In the presence of exenatide, these antibodies cause platelet destruction. If drug-induced thrombocytopenia is suspected, discontinue BYETTA immediately and do not re-expose the patient to exenatide [see Adverse Reactions (6.2) ] .
5.9Acute Gallbladder Disease
Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In a clinical study with exenatide, 1.9% of exenatide-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.
5.10Pulmonary Aspiration During General Anesthesia or Deep Sedation
BYETTA delays gastric emptying [ see Clinical Pharmacology (12.2) ]. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking BYETTA, including whether modifying preoperative fasting recommendations or temporarily discontinuing BYETTA could reduce the incidence of retained gastric contents.
Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking BYETTA.
5.2Never Share a
BYETTA Pen Between Patients BYETTA pe
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Interactions
May impact absorption of orally administered medications. ( 7 )
Warfarin: Postmarketing reports of increased INR sometimes associated with bleeding. Monitor INR frequently until stable upon initiation or alteration of BYETTA therapy. ( 7 ) Generic Section Table 6: Clinically Relevant Interactions with BYETTA Concomitant Use of Insulin Secretagogues or Insulin Clinical Impact Exenatide promotes insulin release from pancreatic beta-cells in the presence of elevated glucose concentrations. The risk of hypoglycemia is increased when exenatide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin [see Warnings and Precautions (5.3) and Adverse Reactions (6) ] . Intervention When initiating BYETTA, consider reducing the dose of concomitantly administered insulin secretagogue or insulin to reduce the risk of hypoglycemia. Warfarin Clinical Impact In a drug interaction study, BYETTA did not have a significant effect on INR [see Clinical Pharmacology (12.3) ] . There have been postmarketing reports for BYETTA of increased INR with concomitant use of warfarin, sometimes associated with bleeding [see Adverse Reactions (6.2) ] . Intervention In patients taking warfarin, the prothrombin time should be monitored more frequently after initiation or alteration of BYETTA therapy. Once a stable prothrombin time has been documented, the prothrombin time can be monitored at the intervals recommended for patients taking warfarin. Orally Administered Drugs (e.g., acetaminophen) Clinical Impact Exenatide slows gastric emptying. Therefore, BYETTA has the potential to reduce the rate of absorption of orally administered drugs [see Clinical Pharmacology (12.3) ]. Intervention Use caution when administering oral medications with BYETTA where a slower rate of oral absorption may be clinically meaningful. For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before 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) ] .
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Limited data with BYETTA in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations ). Based on animal reproduction studies, there may be risks to the fetus from exposure to BYETTA during pregnancy. BYETTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal reproduction studies identified increased adverse fetal and neonatal outcomes from exposure to exenatide during pregnancy and lactation in association with maternal effects. In mice, exenatide administered during gestation and lactation caused increased neonatal deaths at systemic exposure 3-times the human exposure resulting from the maximum recommended human dose (MRHD) of 20 mcg/day for BYETTA (see Data ) .
The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with an HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations Disease-associated maternal and/or embryofetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data In studies evaluating reproduction and development in pregnant mice and rabbits, maternal animals were administered exenatide, the active ingredient in BYETTA, by subcutaneous injection twice a day.
In pregnant mice given 6, 68, 460, or 760 mcg/kg/day exenatide during fetal organogenesis, skeletal variations associated with slowed fetal growth, including changes in number of rib pairs or vertebral ossifications sites, and wavy ribs were observed at 760 mcg/kg/day, a dose that produced maternal toxicity and yielded systemic exposure 390-times the human exposure resulting from the MRHD of BYETTA based on AUC comparison.
In pregnant rabbits given 0.2, 2, 22, 156, or 260 mcg/kg/day exenatide during fetal organogenesis, irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a dose yielding systemic exposure up to 12-times the human exposure from the MRHD of BYETTA based on AUC comparison. In maternal mice given 6, 68, or 760 mcg/kg/day exenatide from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths was observed on postpartum days 2 to 4 in dams given 6 mcg/kg/day, a dose yielding a systemic exposure 3-times the human exposure from the MRHD of BYETTA based on AUC comparison.
Adverse reactions
The following serious adverse reactions are described below or elsewhere in the prescribing information:
Acute Pancreatitis [see Warnings and Precautions (5.1) ]
Never Share a BYETTA Pen Between Patients [see Warnings and Precautions (5.2) ]
Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3) ]
Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions (5.4) ]
Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.5) ]
Immunogenicity [see Warnings and Precautions (5.6) ]
Hypersensitivity [see Warnings and Precautions (5.7) ]
Drug-Induced Thrombocytopenia [see Warnings and Precautions (5.8) ]
Acute Gallbladder Disease [see Warnings and Precautions (5.9) ]
Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.10) ]
Most common (≥5%) and occurring more frequently than placebo in clinical trials: nausea, hypoglycemia, vomiting, diarrhea, feeling jittery, dizziness, headache, dyspepsia, constipation, asthenia. Nausea usually decreases over time. ( 5.3 , 6 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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. Table 1: Incidence (%) and Rate of Hypoglycemia when BYETTA was used as Monotherapy or with Concomitant Antidiabetic Therapy in Six Placebo-Controlled Clinical Trials A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose value consistent with hypoglycemia.
Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a documented blood glucose value <54 mg/dL or prompt recovery after treatment for hypoglycemia. Placebo BID BYETTA 5 mcg BID BYETTA 10 mcg BID Monotherapy (24 Weeks) N 77 77 78 % Overall 1.3% 5.2% 3.8% Rate (episodes/patient-year) 0.03 0.21 0.52 % Severe 0.0% 0.0% 0.0% With Metformin (30 Weeks) N 113 110 113 % Overall 5.3% 4.5% 5.3% Rate (episodes/patient-year) 0.12 0.13 0.12 % Severe 0.0% 0.0% 0.0% With a Sulfonylurea (30 Weeks) N 123 125 129 % Overall 3.3% 14.4% 35.7% Rate (episodes/patient-year) 0.07 0.64 1.61 % Severe 0.0% 0.0% 0.0% With Metformin and a Sulfonylurea (30 Weeks) N 247 245 241 % Overall 12.6% 19.2% 27.8% Rate (episodes/patient-year) 0.58 0.78 1.71 % Severe 0.0% 0.4% 0.0% With a Thiazolidinedione (16 Weeks) N 112 not evaluated 121 % Overall 7.1% not evaluated 10.7% Rate (episodes/patient-years) 0.56 not evaluated 0.98 % Severe 0.0% not evaluated 0.0% With Insulin Glargine with or without Metformin and/or Thiazolidinedione (30 Weeks) When BYETTA was initiated in combination with insulin glargine, the dose of insulin glargine was decreased by 20% in patients with an HbA 1c ≤8.0% to minimize the risk of hypoglycemia.
See Table 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% N = number of Intent-to-Treat subjects in each treatment group. Immunogenicity Antibodies were assessed in 90% of subjects in the 30-week, 24-week, and 16-week studies of 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 1c ) in these patients was generally comparable to that observed in the 534 patients (56%) without antibody titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at 30 weeks. Of these patients, 32 (3% overall) had an attenuated glycemic response to BYETTA; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without antibodies.
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. 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 % Nausea 0 8 Vomiting 0 4 Dyspepsia 0 3 BID = twice daily. 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
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
EXENATIDE SYNTHETIC 600MCG/2.4ML (250MCG/ML)
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
