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BYETTA® (exenatide) injection

BYETTA (exenatide) is a synthetic peptide, glucagon-like peptide-1 (GLP-1) receptor agonist, that was originally identified in the lizard Heloderma suspectum.

Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula C₁₈₄H₂₈₂N₅₀O₆₀S and 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-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2

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 or 10 mcg. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID).

INDICATIONS 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 is not indicated for use in patients with type 1 diabetes.
BYETTA contains exenatide and should not be used with other products containing the active ingredient exenatide.
BYETTA 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. BYETTA 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 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.

DOSAGE AND ADMINISTRATION

Initiate BYETTA at 5 mcg administered subcutaneously twice daily 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 after a meal.
Based on clinical response, the dose of BYETTA can be increased to 10 mcg twice daily after 1 month of therapy.
Administer as a subcutaneous injection in the thigh, abdomen, or upper arm.
Inspect visually for particulate matter and discoloration. Only use BYETTA if the solution appears clear, colorless, and contains no particles.
Do not mix BYETTA with insulin. Do not transfer BYETTA from the pen to a syringe or a vial.
If a dose is missed, resume the treatment regimen as prescribed with the next scheduled dose.

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.
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

Never Share a BYETTA Pen Between Patients: BYETTA pens must never be shared between patients, even if the needle is changed. Pensharingposes a risk for transmission of blood-borne pathogens.

Acute Pancreatitis: Based on postmarketing data, BYETTA has been associated with acute pancreatitis, includingfatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYETTA, andafter dose increases, observe patients carefully for signs and symptoms of pancreatitis (includingpersistent severe abdominal pain, sometimes radiating to the back, which may or may not beaccompanied by vomiting). If pancreatitis is suspected, BYETTA should promptly bediscontinued and appropriate management should be initiated. If pancreatitis is confirmed,BYETTA should not be restarted. Consider antidiabetic therapies other than BYETTA inpatients with a history of pancreatitis.

Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: Patients receiving BYETTA in combination with an insulin secretagogue (e.g., sulfonylurea) orinsulin may have an increased risk of hypoglycemia including severe hypoglycemia.

Acute Kidney Injury: There have been postmarketing reports of altered renal function with BYETTA, includingincreased serum creatinine, renal impairment, worsened chronic renal failure, and acute renalfailure, sometimes requiring hemodialysis or kidney transplantation. Some of these eventsoccurred in patients receiving one or more pharmacologic agents known to affect renal functionor hydration status, such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatorydrugs, or diuretics.

Gastrointestinal Disease: BYETTA has not been studied in patients with severe gastrointestinal disease, includinggastroparesis. Because BYETTA is commonly associated with gastrointestinal adverse reactions,including nausea, vomiting, and diarrhea, the use of BYETTA is not recommended in patientswith severe gastrointestinal disease.

Immunogenicity: Patients may develop antibodies to exenatide following treatment with BYETTA. Antibodylevels were measured in 90% of subjects in the 30-week, 24-week, and 16-week placebocontrolledstudies 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 attenuatedglycemic response. If there is worsening glycemic control or failure to achieve targeted glycemiccontrol, alternative antidiabetic therapy should be considered.

Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxisand angioedema) in patients treated with BYETTA. If a hypersensitivity reaction occurs, thepatient should discontinue BYETTA and other suspect medications and promptly seek medicaladvice. Inform and closely monitor patients with a history of anaphylaxis or angioedema withanother GLP-1 receptor agonist for allergic reactions, because it is unknown whether suchpatients will be predisposed to anaphylaxis with BYETTA.

Drug-Induced Thrombocytopenia: Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopeniahas been reported in the postmarketing setting with exenatide use. Drug-inducedthrombocytopenia is an immune-mediated reaction, with exenatide-dependent anti-plateletantibodies. In the presence of exenatide, these antibodies cause platelet destruction. Ifdrug-induced thrombocytopenia is suspected, discontinue BYETTA immediately and do notre-expose the patient to exenatide.

DRUG INTERACTIONS

Orally Administered Drugs: The effect of BYETTA to slow gastric emptying can reduce the extent and rate of absorption of orally administered drugs. BYETTA should be used with caution in patients receiving oral medications that have narrow therapeutic index or require rapid gastrointestinal absorption. 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

Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin: When initiating BYETTA, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia.

Warfarin: There are postmarketing reports of increased INR sometimes associated with bleeding, withconcomitant use of warfarin and BYETTA. In a drug interactionstudy, BYETTA did not have a significant effect on INR. Inpatients taking warfarin, prothrombin time should be monitored more frequently after initiationor alteration of BYETTA therapy. Once a stable prothrombin time has been documented,prothrombin times can be monitored at the intervals usually recommended for patients onwarfarin.

USE IN SPECIFIC POPULATIONS

Pregnancy: Limited data with BYETTA in pregnant women are not sufficient to determine a drug-associatedrisk for major birth defects or miscarriage. There are risks to the mother and fetus associatedwith poorly controlled diabetes in pregnancy. Based on animalreproduction studies, there may be risks to the fetus from exposure to BYETTA duringpregnancy. BYETTA should be used during pregnancy only if the potential benefit justifies thepotential 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.

Lactation: There is no information regarding the presence of BYETTA, in human milk, the effects ofBYETTA on the breastfed infant, or the effects of BYETTA on milk production. Exenatide waspresent in the milk of lactating mice. However, due to species-specific differences in lactationphysiology, the clinical relevance of these data is not clear. The developmental andhealth benefits of breastfeeding should be considered along with the mother’s clinical need forBYETTA and any potential adverse effects on the breastfed child from BYETTA or from theunderlying maternal condition.

Pediatric Use: The safety and effectiveness of BYETTA have not been established in pediatric patients.

Renal Impairment: BYETTA is not recommended for use in patients with end-stage renal disease or severe renalimpairment (creatinine clearance <30 mL/min) and should be used with caution in patients withrenal transplantation. In patients with end-stage renal disease receiving dialysis, single doses ofBYETTA 5 mcg were not well-tolerated due to gastrointestinal side effects. No dosageadjustment of BYETTA is required in patients with mild renal impairment (creatinine clearance50-80 mL/min). Caution should be applied when initiating or escalating doses of BYETTA from5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min).

OVERDOSAGE

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, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.

BYETTA® (exenatide) injection

BYETTA® (exenatide) injection