Byetta Information
Byetta (Exenatide) Indications And Usage
Byetta (Exenatide) is not a substitute for insulin. Byetta (Exenatide) should not be used for the treatment of type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.
The concurrent use of Byetta (Exenatide) with prandial insulin has not been studied and cannot be recommended.
Based on postmarketing data Byetta (Exenatide) has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Byetta (Exenatide) has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Byetta (Exenatide) . Other antidiabetic therapies should be considered in patients with a history of pancreatitis.
Byetta (Exenatide) Dosage Forms And Strengths
Byetta (Exenatide) is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide in the following packages:
Byetta (Exenatide) Warnings And Precautions
Based on postmarketing data Byetta (Exenatide) has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of Byetta (Exenatide) , and after dose increases, 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, Byetta (Exenatide) should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Byetta (Exenatide) should not be restarted. Consider antidiabetic therapies other than Byetta (Exenatide) in patients with a history of pancreatitis.
The risk of hypoglycemia is increased when Byetta (Exenatide) is used in combination with a sulfonylurea. Therefore, patients receiving Byetta (Exenatide) and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia.
When Byetta (Exenatide) is used in combination with insulin, the dose of insulin should be evaluated. In patients at increased risk of hypoglycemia consider reducing the dose of insulin [s. The concurrent use of Byetta (Exenatide) with prandial insulin has not been studied and cannot be recommended. It is also possible that the use of Byetta (Exenatide) with other glucose-independent insulin secretagogues (e.g. meglitinides) could increase the risk of hypoglycemia.
For additional information on glucose dependent effects
Byetta (Exenatide) should not be used in patients with severe renal impairment (creatinine clearance
There have been postmarketing reports of altered renal function, 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 anti-inflammatory 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 Byetta (Exenatide) . Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.
Byetta (Exenatide) Adverse Reactions
The following additional adverse reactions have been reported during post-approval use of Byetta (Exenatide) . Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, macular or papular rash, angioedema, anaphylactic reaction .
Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding .
Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death .
Neurologic: dysgeusia; somnolence
Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant and kidney transplant dysfunction .
Skin and Subcutaneous Tissue Disorders: alopecia
Byetta (Exenatide) Overdosage
In a clinical study of Byetta (Exenatide) , 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) Description
Byetta (Exenatide) is a synthetic peptide that was originally identified in the lizard Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), biguanides, thiazolidinediones, alpha-glucosidase inhibitors, amylinomimetics and dipeptidyl peptidase-4 inhibitors.
Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula CHNOS 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-NH
Byetta (Exenatide) is supplied for SC injection 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).
Byetta (Exenatide) Clinical Pharmacology
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 (Exenatide) 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.
Byetta (Exenatide) improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.
Glucose-dependent insulin secretion: Byetta (Exenatide) has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. However, Byetta (Exenatide) does not impair the normal glucagon response to hypoglycemia.
First-phase insulin response: In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of Byetta (Exenatide) at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with Byetta (Exenatide) compared with saline (p
Figure 1: Mean (+SEM) Insulin Secretion Rate During Infusion of Byetta (Exenatide) or Saline in Patients With Type 2 Diabetes and During Infusion of Saline in Healthy Subjects
Glucagon secretion: In patients with type 2 diabetes, Byetta (Exenatide) moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand.
Gastric emptying: Byetta (Exenatide) slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.
Food intake: In both animals and humans, administration of exenatide has been shown to reduce food intake.
Byetta (Exenatide) Nonclinical Toxicology
A 104-week carcinogenicity study was conducted in male and female rats at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC 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 with systemic exposures of 5, 22, and 130 times, respectively, the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on plasma area under the curve (AUC).
In a 104-week carcinogenicity study in mice at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 95 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Exenatide was 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 SC 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 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7, there were no adverse fetal effects at doses up to 760 mcg/kg/day, systemic exposures up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 (organogenesis), cleft palate (some with holes) and irregular fetal skeletal ossification of rib and skull bones were observed at 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 (organogenesis), irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a systemic exposure 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths was observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Byetta (Exenatide) Clinical Studies
Byetta (Exenatide) has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, a combination of metformin and a thiazolidinedione, or in combination with insulin glargine with or without metformin and/or thiazolidinedione.
In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, Byetta (Exenatide) 5 mcg BID (n = 77), Byetta (Exenatide) 10 mcg BID (n = 78), or placebo BID (n = 77) was used as monotherapy in patients with entry HbA ranging from 6.5-10%. All patients assigned to Byetta (Exenatide) initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive Byetta (Exenatide) 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. Byetta (Exenatide) or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were Caucasian, 26% were West Asian, 3% were Hispanic, 3% were Black, and 0.4% were East Asian.
The primary endpoint was the change in HbA from baseline to Week 24 (or the last value at time of early discontinuation). Compared to placebo, Byetta (Exenatide) 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in HbA from baseline at Week 24 (Table 6).
On average, there were no adverse effects of exenatide on blood pressure or lipids.
Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of Byetta (Exenatide) in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea. In addition, a 16-week, placebo-controlled trial was conducted where Byetta (Exenatide) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control.
In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned to receive Byetta (Exenatide) 5 mcg BID, Byetta (Exenatide) 10 mcg BID, or placebo BID before the morning and evening meals, in addition to their existing oral antidiabetic agent. All patients assigned to Byetta (Exenatide) initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive Byetta (Exenatide) 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the study. A total of 1446 patients were randomized in the three 30-week trials: 991 (69%) were Caucasian, 224 (16%) were Hispanic, and 174 (12%) were Black. Mean HbA values at baseline for the trials ranged from 8.2% to 8.7%.
In the placebo-controlled trial of 16 weeks duration, Byetta (Exenatide) (n = 121) or placebo (n = 112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin. Randomization to Byetta (Exenatide) or placebo was stratified based on whether the patients were receiving metformin. Byetta (Exenatide) treatment was initiated at a dose of 5 mcg BID for 4 weeks then increased to 10 mcg BID for 12 more weeks. Patients assigned to placebo received placebo BID throughout the study. Byetta (Exenatide) or placebo was injected subcutaneously before the morning and evening meals. In this trial, 79% of patients were taking a thiazolidinedione and metformin and 21% were taking a thiazolidinedione alone. The majority of patients (84%) were Caucasian, 8% were Hispanic and 3% were Black. The mean baseline HbA values were 7.9% for Byetta (Exenatide) and placebo.
The primary endpoint in each study was the mean change in HbA from baseline to study end (or early discontinuation). Table 7 summarizes the study results for the 30-week and 16-week clinical trials.
A 30-week, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of Byetta (Exenatide) (n = 137) versus placebo (n = 122) when added to titrated insulin glargine, with or without metformin and/or thiazolidinedione, in patients with type 2 diabetes with inadequate glycemic control.
All patients assigned to Byetta (Exenatide) initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients assigned to Byetta (Exenatide) had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. Byetta (Exenatide) or placebo was injected subcutaneously before the morning and evening meals. Patients with an HbA ≤8.0% decreased their prestudy dose of insulin glargine by 20% and patients with an HbA ≥8.1% maintained their current dose of insulin glargine. Five weeks after initiating randomized treatment, insulin doses were titrated with guidance from the investigator toward predefined fasting glucose targets according to the dose titration algorithm provided in Table 9. The majority of patients (78%) were Caucasian, 10% were American Indian or Alaska Native, 9% were Black, 3% were Asian, and 0.8% were of multiple origins.
The primary endpoint was the change in HbA from baseline to Week 30. Compared to placebo, Byetta (Exenatide) 10 mcg BID resulted in statistically significant reductions in HbA from baseline at Week 30 (Table 8) in patients receiving titrated insulin glargine.
Byetta (Exenatide) How Supplied/storage And Handling
Byetta (Exenatide) is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide.
The following packages are available:5 mcg per dose, 60 doses, 1.2 mL prefilled pen, NDC 66780-210-0710 mcg per dose, 60 doses, 2.4 mL prefilled pen, NDC 66780-212-01
Byetta (Exenatide) Patient Counseling Information
Patients should be informed of the potential risks and benefits of Byetta (Exenatide) and of alternative modes of therapy. Patients should also be fully informed about self-management practices, including the importance of proper storage of Byetta (Exenatide) , injection technique, timing of dosage of Byetta (Exenatide) and concomitant oral drugs, adherence to meal planning, regular physical activity, periodic blood glucose monitoring and HbA testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications.
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