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Risk Of Thyroid C-cell Tumors
In both genders of rats, exenatide extended-release caused a dose-related and treatment-durationdependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures compared to controls [see Nonclinical Toxicology]. A statistically significant increase in malignant thyroid C-cell carcinomas was observed in female rats receiving exenatide extended-release at 25-times clinical exposure compared to controls and higher incidences were noted in males above controls in all treated groups at ≥ 2-times clinical exposure. The potential of exenatide extended-release to induce C-cell tumors in mice has not been evaluated. Other GLP-1 receptor agonists have also induced thyroid C-cell adenomas and carcinomas in male and female mice and rats at clinically relevant exposures. It is unknown whether BYDUREON will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of exenatide extended-release-induced rodent thyroid C-cell tumors has not been determined.
Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.
BYDUREON is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk of MTC with the use of BYDUREON and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dsyphagia, dyspnea, persistent hoarseness).
Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with BYDUREON. Such monitoring may increase the risk of unnecessary procedures, due to the low specificity of serum calcitonin testing for MTC and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have values > 50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
Based on postmarketing data, exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYDUREON, 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, BYDUREON should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, BYDUREON should not be restarted. Consider antidiabetic therapies other than BYDUREON in patients with a history of pancreatitis.
Hypoglycemia With Concomitant Use Of Insulin Secretagogues Or Insulin
The risk of hypoglycemia is increased when exenatide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Patients may require a lower dose of the secretagogue or insulin to reduce the risk of hypoglycemia in this setting [see ADVERSE REACTIONS].
BYDUREON 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]. 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 BYDUREON may induce nausea and vomiting with transient hypovolemia, treatment may worsen renal function. Use BYDUREON with caution in patients with moderate renal impairment (creatinine clearance 30-50 mL/min) [see Use In Specific Populations and CLINICAL PHARMACOLOGY]. BYDUREON has not been studied in patients with end-stage renal disease or severe renal impairment.
There have been postmarketing reports of altered renal function with exenatide, 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 antiinflammatory 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 exenatide. Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.
Exenatide has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Because exenatide is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea, the use of BYDUREON is not recommended in patients with severe gastrointestinal disease.
Patients may develop antibodies to exenatide following treatment with BYDUREON. Antiexenatide antibodies were measured in all BYDUREON-treated patients in the five comparatorcontrolled 24- to 30-week studies of BYDUREON. In 6% of BYDUREON-treated patients, 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].
There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) in patients treated with exenatide. If a hypersensitivity reaction occurs, the patient should discontinue BYDUREON and other suspect medications and promptly seek medical advice [see ADVERSE REACTIONS].
There have been postmarketing reports of serious injection-site reactions (e.g., abscess, cellulitis, and necrosis), with or without subcutaneous nodules, with the use of BYDUREON. Isolated cases required surgical intervention [see ADVERSE REACTIONS].
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYDUREON or any other antidiabetic drug.
Patient Counseling Information
See FDA-approved Medication Guide. Prior to initiation of BYDUREON, patients should be trained by their healthcare professional.
Inform patients about the potential risks and benefits of BYDUREON and of alternative modes of therapy. Also inform patients about the importance of diabetes self-management practices, such as regular physical activity, adhering to meal planning, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications.
Risk Of Thyroid C-cell Tumors
Inform patients that exenatide extended-release causes benign and malignant thyroid C-cell tumors in rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia, or dyspnea) to their physician [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
Risk Of Pancreatitis
Inform patients treated with BYDUREON of the potential risk for pancreatitis. Explain 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. Instruct patients to discontinue BYDUREON promptly and contact their healthcare provider if persistent severe abdominal pain occurs [see WARNINGS AND PRECAUTIONS].
Risk Of Hypoglycemia
The risk of hypoglycemia is increased when BYDUREON is used in combination with an agent that induces hypoglycemia, such as a sulfonylurea or insulin [see WARNINGS AND PRECAUTIONS]. Explain the symptoms, treatment, and conditions that predispose to the development of hypoglycemia. While the patient's usual instructions for hypoglycemia management do not need to be changed, these instructions should be reviewed and reinforced when initiating BYDUREON therapy, particularly when concomitantly administered with a sulfonylurea or insulin [see WARNINGS AND PRECAUTIONS].
Risk Of Renal Impairment
Inform patients treated with BYDUREON of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs [see WARNINGS AND PRECAUTIONS].
Risk Of Hypersensitivity Reactions
Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of exenatide. If symptoms of hypersensitivity reactions occur, patients must stop taking BYDUREON and seek medical advice promptly [see WARNINGS AND PRECAUTIONS].
Risk Of Injection-Site Reactions
Inform patients that there have been postmarketing reports of serious injection-site reactions with or without subcutaneous nodules, with the use of BYDUREON. Isolated cases of injection-site reactions required surgical intervention. Advise patients to seek medical advice if symptomatic nodules occur, or for any signs or symptoms of abscess, cellulitis, or necrosis [see WARNINGS AND PRECAUTIONS].
Use In Pregnancy
Advise patients to inform their healthcare provider if they are pregnant or intend to become pregnant [see Use in Specific Populations].
Patients should be trained on how to use BYDUREON properly prior to self-administration. Instruct patients on proper mixing and injection technique to ensure the product is adequately mixed and a full dose is delivered. Refer patients to the accompanying Instructions for Use for complete administration instructions with illustrations.
Each dose of BYDUREON should be administered as a subcutaneous injection at any time on the dosing day, with or without meals. Patients should be informed that the day of once every 7 days (weekly) administration can be changed if necessary as long as the last dose was administered 3 or more days before. If a dose is missed, it should be administered as soon as noticed, provided the next regularly scheduled dose is due at least 3 days later. Thereafter, patients can resume their usual once every 7 days (weekly) dosing schedule. If a dose is missed and the next regularly scheduled dose is due in 1 or 2 days, the patient should not administer the missed dose and instead resume BYDUREON with the next regularly scheduled dose [see DOSAGE AND ADMINISTRATION].
Counsel patients that they should never share BYDUREON with another person, even if the needle is changed. Sharing of BYDUREON or needles between patients may pose a risk of transmission of infection.
If a patient is currently taking BYETTA, it should be discontinued upon starting BYDUREON. Patients formerly on BYETTA who start BYDUREON may experience transient elevations in blood glucose concentrations, which generally improve within the first 2 weeks after initiation of therapy [see DOSAGE AND ADMINISTRATION and Clinical Studies].
Treatment with BYDUREON may also result in nausea, particularly upon initiation of therapy [see ADVERSE REACTIONS].
The patient should read the BYDUREON Medication Guide and the Instructions for Use before starting BYDUREON therapy and review them each time the prescription is refilled.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
A 104-week carcinogenicity study was conducted with exenatide extended-release in male and female rats at doses of 0.3, 1.0, and 3.0 mg/kg (2-, 9-, and 26-times human systemic exposure based on AUC, respectively) administered by subcutaneous injection every other week. A statistically significant increase in thyroid C-cell tumor incidence was observed in both males and females. The incidence of C-cell adenomas was statistically significantly increased at all doses (27%-31%) in females and at 1.0 and 3.0 mg/kg (46% and 47%, respectively) in males compared with the control group (13% for males and 7% for females). A statistically significantly higher incidence of C-cell carcinomas occurred in the high-dose group females (6%), while numerically higher incidences of 3%, 7%, and 4% (nonstatistically significant versus controls) were noted in the low-, mid-, and high-dose group males compared with the control group (0% for both males and females). An increase in benign fibromas was seen in the skin subcutis at injection sites of males given 3 mg/kg. No treatment-related injection-site fibrosarcomas were observed at any dose. The human relevance of these findings is currently unknown.
A 104-week carcinogenicity study was conducted with exenatide, the active ingredient in BYDUREON, in male and female rats at doses of 18, 70, or 250 mcg/kg/day (3-, 6-, and 27- times human systemic exposure based on AUC, respectively) administered by once-daily bolus subcutaneous 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.
In a 104-week carcinogenicity study with exenatide, the active ingredient in BYDUREON, in male and female mice at doses of 18, 70, or 250 mcg/kg/day administered by once-daily bolus subcutaneous injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 16 times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC. The carcinogenicity of exenatide extended-release has not been evaluated in mice.
BYDUREON and exenatide, the active ingredient in BYDUREON, were 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 exenatide, the active ingredient in BYDUREON, at twice-daily subcutaneous 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 148 times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of BYDUREON use in pregnant women. In rats, exenatide extended-release administered during the major period of organogenesis reduced fetal growth and produced skeletal ossification deficits in association with maternal effects; exenatide extended-release was not teratogenic in rats. In animal developmental studies, exenatide, the active ingredient of BYDUREON, caused cleft palate, irregular skeletal ossification, and an increased number of neonatal deaths. BYDUREON should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Fetuses from pregnant rats given subcutaneous doses of exenatide extended-release at 0.3, 1, or 3 mg/kg on gestation days 6, 9, 12, and 15 demonstrated reduced fetal growth at all doses and produced skeletal ossification deficits at 1 and 3 mg/kg in association with maternal effects (decreased food intake and decreased body weight gain). There was no evidence of malformations. Doses of 0.3, 1, and 3 mg/kg correspond to systemic exposures of 3, 7, and 17 times, respectively, the human exposure resulting from the recommended dose of 2 mg/week, based on area under the time-concentration curve (AUC) [see Nonclinical Toxicology].
Female mice given subcutaneous doses of exenatide, the active ingredient of BYDUREON, at 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 148 times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC [see Nonclinical Toxicology].
In developmental toxicity studies, pregnant animals received exenatide, the active ingredient of BYDUREON, subcutaneously during organogenesis. Specifically, fetuses from pregnant rabbits given subcutaneous doses of exenatide at 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 4 times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC. Fetuses from pregnant mice given subcutaneous doses of exenatide at 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 that is equivalent to the human exposure resulting from the recommended dose of 2 mg/week, based on AUC [see Nonclinical Toxicology].
Lactating mice given subcutaneous doses of exenatide, the active ingredient of BYDUREON, at 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 to 4 in dams given 6 mcg/kg/day, a systemic exposure that is equivalent to the human exposure resulting from the recommended dose of 2 mg/week, based on AUC [see Nonclinical Toxicology].
A Pregnancy Registry has been implemented to monitor pregnancy outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling 1-800- 633-9081.
Exenatide is present in the milk of lactating mice at concentrations less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing. It is not known whether exenatide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for exenatide extended-release in animal studies, a decision should be made whether to discontinue nursing or to discontinue BYDUREON, taking into account the importance of the drug to the mother.
Safety and effectiveness of BYDUREON have not been established in pediatric patients. BYDUREON is not recommended for use in pediatric patients.
In the five comparator-controlled 24- to 30-week trials, BYDUREON was studied in 132 patients (16.6%) who were at least 65 years old and 20 patients who were at least 75 years old. No differences in safety (N=152) and efficacy (N=52) were observed between these patients and younger patients, but the small sample size for patients ≥ 75 years old limits conclusions.
In separate trials, BYETTA was studied in 282 patients at least 65 years old and in 16 patients at least 75 years old. No differences in safety and efficacy were observed between these patients and younger patients, but the small sample size for patients ≥ 75 years old limits conclusions.
Because elderly patients are more likely to have decreased renal function, use caution when initiating BYDUREON in the elderly.
BYDUREON 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. Use BYDUREON with caution in patients with moderate renal impairment (creatinine clearance 30-50 mL/min) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
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 impairment is not expected to affect blood concentrations of exenatide [see CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 10/26/2015
Additional Bydureon Information
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