BYDUREON® (exenatide extended-release) for injectable suspension

BYDUREON® (exenatide extended-release) for injectable suspension

BYDUREON® (exenatide extended-release) for injectable suspension

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.

H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile­Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2

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.

The diluent for the BYDUREON vial is supplied in a prefilled syringe within each single-dose tray. The diluent for the BYDUREON Pen is contained within each single-dose pen. Each configuration contains sufficient diluent to deliver 0.65 mL. The diluent is a clear, colorless to pale-yellow solution composed of carboxymethylcellulose sodium (19 mg), polysorbate 20 (0.63 mg), sodium phosphate monobasic monohydrate (0.61 mg), sodium phosphate dibasic heptahydrate (0.51 mg), sodium chloride (4.1 mg), and water for injection. Sodium hydroxide may be added during manufacture of BYDUREON Pen for pH adjustment.

INDICATIONS

BYDUREON is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.

Limitations of Use:

  • BYDUREON is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of the rat thyroid C-cell tumor findings to humans.
  • BYDUREON is not indicated for use in patients with type 1 diabetes mellitus.
  • BYDUREON is an extended-release formulation of exenatide and should not be used with other products containing the active ingredient exenatide.
  • BYDUREON 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.

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DOSAGE AND ADMINISTRATION

  • The recommended dose of BYDUREON is 2 mg subcutaneously once every 7 days (weekly). The dose can be administered at any time of day, with or without meals.
  • Discontinue an immediate-or extended-release exenatide product prior to initiation of BYDUREON. Patients changing from immediate-release exenatide to BYDUREON may experience transient (approximately 2 to 4 weeks) elevations in blood glucose concentrations.
  • The day of weekly administration can be changed, if necessary, as long as the last dose was administered 3 or more days before the new day of administration.
  • If a dose is missed, administer the dose as soon as noticed, provided the next regularly scheduled dose is due at least 3 days later. Thereafter, patients can resume their usual dosing schedule of once every 7 days (weekly).
  • If a dose is missed and the next regularly scheduled dose is due 1 or 2 days later, do not administer the missed dose and instead resume BYDUREON with the next regularly scheduled dose.

Administration Instructions

  • There are two presentations of BYDUREON (i.e., a single dose tray and a single dose pen). Each presentation of BYDUREON requires constitution prior to use to obtain a final concentration of 2 mg of exenatide per 0.65 mL of suspension.
  • Prior to initiation, train patients and caregivers on proper mixing and injection. Instruct caregivers to assist pediatric patients with mixing and administration.
  • Inspect BYDUREON visually before use. The suspension should appear white to off-white and cloudy. Do not use if particulate matter is present or if discoloration is observed.
  • Immediately after the dose is prepared, administer BYDUREON subcutaneously to the abdomen, thigh, or upper arm region. Instruct patients to use a different injection site each week when injecting in the same region.
  • When using BYDUREON with insulin, always administer BYDUREON and insulin as separate injections and never mix the products. It is acceptable to inject BYDUREON and insulin in the same body region but the injections should not be adjacent to each other.

CONTRAINDICATIONS

BYDUREON is contraindicated in patients with:

  • A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
  • A prior serious hypersensitivity reaction to exenatide or to any of the excipients in BYDUREON. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with BYDUREON.
  • 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.

WARNINGS AND PRECAUTIONS

Risk of Thyroid C-cell Tumors: In both genders of rats, exenatide extended-release caused a dose-related and treatment-duration– dependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures compared to controls. 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, dysphagia, dyspnea, persistent hoarseness).

Acute Pancreatitis: 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: Patients receiving BYDUREON in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia.

Acute Kidney Injury: BYDUREON may induce nausea and vomiting with transient hypovolemia and may worsen renal function. 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.

Gastrointestinal Disease: 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.

Immunogenicity: Patients may develop antibodies to exenatide following treatment with BYDUREON.

Hypersensitivity: 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 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 BYDUREON.

Drug-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 BYDUREON immediately and do not re-expose the patient to exenatide. Upon discontinuation, thrombocytopenia can persist due to the prolonged exenatide exposure from BYDUREON (about 10 weeks).

Injection-Site 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.

Acute Gallbladder Disease: Acute events of gallbladder disease, such as cholelithiasis or cholecystitis, have been reported in GLP-1 receptor agonist trials and postmarketing. In the EXSCEL trial.

DRUG INTERACTIONS

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.

When initiating BYDUREON, consider reducing the dose of concomitantly administered insulin secretagogue or insulin to reduce the risk of hypoglycemia.

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.

In patients taking warfarin, the INR should be monitored more frequently after initiating BYDUREON. Once a stable INR has been documented, the INR can be monitored at the intervals usually recommended for patients on warfarin.

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.

Use caution when administering oral medications with BYDUREON where a slower rate of oral absorption may be clinically meaningful.

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. BYDUREON should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

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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: The safety and effectiveness of BYDUREON as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. Use of BYDUREON for this indication is supported by a 24-week placebo-controlled trial with 28-week open-label uncontrolled extension in 82 pediatric patients aged 10 to less than 18 years with type 2 diabetes, a pediatric pharmacokinetic study, and studies in adults with type 2 diabetes mellitus.

The safety and effectiveness of BYDUREON have not been established in pediatric patients less than 10 years of age.

Renal Impairment

Pharmacokinetic studies of renally impaired adult patients receiving BYDUREON indicate that there is an increase in exposure in moderate and mild renally impaired patients as compared to patients with normal renal function. BYDUREON may induce nausea and vomiting with transient hypovolemia and may worsen renal function.

Monitor patients with mild renal impairment for adverse reactions that may lead to hypovolemia. BYDUREON is not recommended for use in patients with eGFR below 45 mL/min/1.73 m2 or end stage renal disease. If used in patients with renal transplantation, closely monitor for adverse reactions that may lead to hypovolemia.

OVERDOSAGE

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.

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