BYDUREON® (exenatide extended-release)
BYDUREON (exenatide extended-release) for injectable suspension is a GLP-1 receptor agonist supplied as a sterile powder to be suspended in diluent and administered by subcutaneous injection. Exenatide is a 39-amino acid synthetic peptide amide with an empirical formula of C184H282N50O60S and a molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below.
BYDUREON is a white to off-white powder that is available in a dosage strength of 2 mg exenatide per vial or per pen. Exenatide is incorporated in an extended-release microsphere formulation containing the 50:50 poly(D,L-lactide-co-glycolide) polymer (37.2 mg per dose) along with sucrose (0.8 mg per dose). The powder must be suspended in the diluent prior to injection.
Indications and usage
BYDUREON 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
Limitations of Use:
- Not recommended as first-line therapy for patients inadequately controlled on diet and exercise
- Should not be used to treat type 1 diabetes or diabetic ketoacidosis
- Use with prandial insulin has not been studied
- BYDUREON is an extended-release formulation of exenatide. Do not coadminister with other exenatide containing products.
- Has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
Mechanism of Action
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. BYDUREON 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 is a GLP-1 receptor agonist that has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide promotes insulin release from pancreatic beta-cells in the presence of elevated glucose concentrations.
Dosage and administration
- Administer 2 mg by subcutaneous injection once every seven days (weekly), at any time of day and with or without meals.
- Administer immediately after the dose is prepared.
- Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.
- Prior serious hypersensitivity reaction to exenatide or any of the product components.
Warnings and precautions
Exenatide extended-release causes thyroid C-cell tumors at clinically relevant exposures in rats. It is unknown whether BYDUREON causes 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
BYDUREON is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and the symptoms of thyroid tumors.
Acute Pancreatitis: Including fatal and non-fatal hemorrhagic or necrotizing pancreatitis has been reported. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed. Consider other antidiabetic therapies if patient has history of pancreatitis.
Hypoglycemia: When used in combination with an insulin secretagogue (e.g., a sulfonylurea) or insulin, consider lowering dose of the secretagogue or insulin to reduce risk of hypoglycemia.
Acute Kidney Injury and Impairment of Renal Function: Sometimes requiring hemodialysis and kidney transplantation have been reported. Not recommended if patient has severe renal impairment or end-stage renal disease. Use with caution in patients with renal transplantation or moderate renal impairment.
Gastrointestinal Disease: Not recommended in patients with severe gastrointestinal disease (e.g., gastroparesis).
Immunogenicity: Patients may develop antibodies to exenatide. If there is worsening glycemic control or failure to achieve target glycemic control, consider alternative antidiabetic therapy.
Hypersensitivity: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. In such cases, patients are to discontinue BYDUREON and promptly seek medical advice.
Injection-site Reactions: Serious injection-site reactions with or without subcutaneous nodules have been reported
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYDUREON.
Most common (≥5%) and occurring more frequently than comparator in clinical trials: nausea, diarrhea, headache, vomiting, constipation, injectionsite pruritus, injection-site nodule, and dyspepsia.
Orally Administered Drugs (e.g., acetaminophen): Exenatide slows gastric emptying. Therefore, BYDUREON has the potential to reduce the rate of absorption of orally administered drugs.
Warfarin: BYDUREON has not been studied with warfarin. However, in a drug interaction study, BYETTA did not have a significant effect on INR. There have been postmarketing reports for exenatide of increased INR with concomitant use of warfarin, sometimes associated with bleeding.
Concomitant Use of Insulin Secretagogues or Insulin: 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.
Use in specific populations
Pregnancy: Limited data with exenatide, the active ingredient in BYDUREON, 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.
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Lactation: There is no information regarding the presence of exenatide in human milk, the effects of exenatide on the breastfed infant, or the effects of exenatide on milk production. Exenatide, the active ingredient in BYDUREON, was present in the milk of lactating mice. However, due to species-specific differences in lactation physiology, the clinical relevance of these data is not clear.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for exenatide and any potential adverse effects on the breastfed child from exenatide or from the underlying maternal condition.
Pediatric Use: Safety and effectiveness of BYDUREON have not been established in pediatric patients. BYDUREON is not recommended for use in pediatric patients.
Effects of overdoses with BYETTA, another formulation of exenatide, included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations, including severe hypoglycemia requiring parenteral glucose administration. In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.
Storage and Handling
- BYDUREON should be stored in the refrigerator at 36°F to 46°F (2°C to 8°C), up to the expiration date or until preparing for use. BYDUREON should not be used past the expiration date. The expiration date can be found on the carton, on the cover of the single-dose tray, or on the pen label.
- Do not freeze BYDUREON. Do not use BYDUREON if it has been frozen. Protect from light.
- BYDUREON can be kept at room temperature not to exceed 77°F (25°C) [see USP Controlled Room Temperature] for no more than a total of 4 weeks, if needed.
- Use the diluent only if it is clear and free of particulate matter.
- After suspension, the mixture should be white to off-white and cloudy.
- BYDUREON must be administered immediately after the exenatide powder is suspended in the diluent.
- Use a puncture-resistant container to discard BYDUREON with the needle still attached. Do not reuse or share needles or syringes.
- Keep out of the reach of children.