Generic Name: exenatide
Dosage Form: injection
FULL PRESCRIBING INFORMATION
Indications and Usage for Byetta
Type 2 Diabetes Mellitus
Byetta is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Important Limitations of Use
Byetta is not a substitute for insulin. Byetta 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 with prandial insulin has not been studied and cannot be recommended.
Based on postmarketing data Byetta has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Byetta 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. Other antidiabetic therapies should be considered in patients with a history of pancreatitis.
Byetta Dosage and Administration
Recommended Dosing
Byetta should be initiated at 5 mcg administered 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). Byetta should not be administered after a meal. Based on clinical response, the dose of Byetta can be increased to 10 mcg twice daily after 1 month of therapy. Initiation with 5 mcg reduces the incidence and severity of gastrointestinal side effects. Each dose should be administered as a subcutaneous (SC) injection in the thigh, abdomen, or upper arm. Do not mix Byetta with insulin. Do not transfer Byetta from the pen to a syringe or a vial. No data are available on the safety or efficacy of intravenous or intramuscular injection of Byetta.
Use Byetta only if it is clear, colorless and contains no particles.
Dosage Forms and Strengths
Byetta is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide in the following packages:
- 5 mcg per dose, 60 doses, 1.2 mL prefilled pen
- 10 mcg per dose, 60 doses, 2.4 mL prefilled pen
Contraindications
Hypersensitivity
Byetta is contraindicated in patients with prior severe hypersensitivity reactions to exenatide or to any of the product components.
Warnings and Precautions
Acute Pancreatitis
Based on postmarketing data Byetta has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of Byetta, 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 should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Byetta should not be restarted. Consider antidiabetic therapies other than Byetta in patients with a history of pancreatitis.
Use with Medications Known to Cause Hypoglycemia
The risk of hypoglycemia is increased when Byetta is used in combination with a sulfonylurea. Therefore, patients receiving Byetta and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia.
When Byetta 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 [see Adverse Reactions (6.1)]. The concurrent use of Byetta with prandial insulin has not been studied and cannot be recommended. It is also possible that the use of Byetta with other glucose-independent insulin secretagogues (e.g. meglitinides) could increase the risk of hypoglycemia.
For additional information on glucose dependent effects see Mechanism of Action (12.1).
Renal Impairment
Byetta 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 (8.6)]. 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 Byetta may induce nausea and vomiting with transient hypovolemia, treatment may worsen renal function. Caution should be applied when initiating or escalating doses of Byetta from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min).
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 has not been found to be directly nephrotoxic in preclinical or clinical studies.
Gastrointestinal Disease
Byetta has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Because Byetta is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea, the use of Byetta is not recommended in patients with severe gastrointestinal disease.
Immunogenicity
Patients may develop antibodies to exenatide following treatment with Byetta. Antibody levels were measured in 90% of subjects in the 30-week, 24-week and 16-week studies of Byetta. In 3%, 4% and 1% of these patients, respectively, 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 (6.1)].
Hypersensitivity
There have been postmarketing reports of serious hypersensitivity reactions (e.g. anaphylaxis and angioedema) in patients treated with Byetta. If a hypersensitivity reaction occurs, the patient should discontinue Byetta and other suspect medications and promptly seek medical advice [see Adverse Reactions (6.2)].
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Byetta or any other antidiabetic drug.
Adverse Reactions
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Hypoglycemia
Table 1 summarizes the incidence and rate of hypoglycemia with Byetta in six placebo-controlled clinical trials.
| Byetta | |||
|---|---|---|---|
| Placebo twice daily | 5 mcg twice daily | 10 mcg twice daily | |
| N = The number of Intent-to-Treat subjects in each treatment group. | |||
| |||
| Monotherapy (24 Weeks) | |||
| N | 77 | 77 | 78 |
| % Overall | 1.3% | 5.2% | 3.8% |
| Rate (episodes/patient-year) | 0.03 | 0.21 | 0.52 |
| % Severe | 0.0% | 0.0% | 0.0% |
| With Metformin (30 Weeks) | |||
| N | 113 | 110 | 113 |
| % Overall | 5.3% | 4.5% | 5.3% |
| Rate (episodes/patient-year) | 0.12 | 0.13 | 0.12 |
| % Severe | 0.0% | 0.0% | 0.0% |
| With a Sulfonylurea (30 Weeks) | |||
| N | 123 | 125 | 129 |
| % Overall | 3.3% | 14.4% | 35.7% |
| Rate (episodes/patient-year) | 0.07 | 0.64 | 1.61 |
| % Severe | 0.0% | 0.0% | 0.0% |
| With Metformin and a Sulfonylurea (30 Weeks) | |||
| N | 247 | 245 | 241 |
| % Overall | 12.6% | 19.2% | 27.8% |
| Rate (episodes/patient-year) | 0.58 | 0.78 | 1.71 |
| % Severe | 0.0% | 0.4% | 0.0% |
| With a Thiazolidinedione (16 Weeks) | |||
| N | 112 | not evaluated | 121 |
| % Overall | 7.1% | not evaluated | 10.7% |
| Rate (episodes/patient-years) | 0.56 | not evaluated | 0.98 |
| % Severe | 0.0% | not evaluated | 0.0% |
| With Insulin Glargine (30 Weeks) † | |||
| N | 122 | not evaluated | 137 |
| % Overall | 29.5% | not evaluated | 24.8% |
| Rate (episodes/patient-years) | 1.58 | not evaluated | 1.61 |
| % Severe | 0.8% | not evaluated | 0.0% |
Immunogenicity
Antibodies were assessed in 90% of subjects in the 30-week, 24-week and 16-week studies of Byetta. In the 30-week controlled trials of Byetta add-on to metformin and/or sulfonylurea, antibodies were assessed at 2- to 6-week intervals. The mean antibody titer peaked at week 6 and was reduced by 55% by week 30. Three hundred and sixty patients (38%) had low titer antibodies (<625) to exenatide at 30 weeks. The level of glycemic control (HbA1c) in these patients was generally comparable to that observed in the 534 patients (56%) without antibody titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at 30 weeks. Of these patients, 32 (3% overall) had an attenuated glycemic response to Byetta; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without antibodies [see Warnings and Precautions (5.5)].
In the 16-week trial of Byetta add-on to thiazolidinediones, with or without metformin, 36 patients (31%) had low titer antibodies to exenatide at 16 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 69 patients (60%) without antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks. Of these patients, 4 (4% overall) had an attenuated glycemic response to Byetta; the remaining 6 (5% overall) had a glycemic response comparable to that of patients without antibodies [see Warnings and Precautions (5.5)].
In the 24-week trial of Byetta used as monotherapy, 40 patients (28%) had low titer antibodies to exenatide at 24 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 101 patients (70%) without antibody titers. An additional 3 patients (2%) had higher titer antibodies at 24 weeks. Of these patients, 1 (1% overall) had an attenuated glycemic response to Byetta; the remaining 2 (1% overall) had a glycemic response comparable to that of patients without antibodies [see Warnings and Precautions (5.5)].
Antibodies to exenatide were not assessed in the 30-week trial of Byetta used in combination with insulin glargine.
Two hundred and ten patients with antibodies to exenatide in the Byetta clinical trials were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. No treatment-emergent cross reactive antibodies were observed across the range of titers.
Other Adverse Reactions
Monotherapy
For the 24-week placebo-controlled study of Byetta used as a monotherapy, Table 2 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in Byetta-treated patients compared with placebo-treated patients.
| Monotherapy | Placebo BID N = 77 % | All Byetta BID N = 155 % |
|---|---|---|
| BID = twice daily. | ||
| ||
| Nausea | 0 | 8 |
| Vomiting | 0 | 4 |
| Dyspepsia | 0 | 3 |
Adverse reactions reported in ≥1.0 to <2.0% of patients receiving Byetta and reported more frequently than with placebo included decreased appetite, diarrhea, and dizziness. The most frequently reported adverse reaction associated with Byetta, nausea, occurred in a dose-dependent fashion.
Two of the 155 patients treated with Byetta withdrew due to adverse reactions of headache and nausea. No placebo-treated patients withdrew due to adverse reactions.
Combination Therapy
Add-on to metformin and/or sulfonylurea
In the three 30-week controlled trials of Byetta add-on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence ≥2% and occurring more frequently in Byetta-treated patients compared with placebo-treated patients [see Warnings and Precautions (5.2)] are summarized in Table 3.
| Placebo BID N = 483 % | All Byetta BID N = 963 % | |
|---|---|---|
| BID = twice daily. | ||
| ||
| Nausea | 18 | 44 |
| Vomiting | 4 | 13 |
| Diarrhea | 6 | 13 |
| Feeling Jittery | 4 | 9 |
| Dizziness | 6 | 9 |
| Headache | 6 | 9 |
| Dyspepsia | 3 | 6 |
| Asthenia | 2 | 4 |
| Gastroesophageal Reflux Disease | 1 | 3 |
| Hyperhidrosis | 1 | 3 |
Adverse reactions reported in ≥1.0 to <2.0% of patients receiving Byetta and reported more frequently than with placebo included decreased appetite. Nausea was the most frequently reported adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced nausea. Patients in the long-term uncontrolled open-label extension studies at 52 weeks reported no new types of adverse reactions than those observed in the 30-week controlled trials.
The most common adverse reactions leading to withdrawal for Byetta-treated patients were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew due to nausea and none due to vomiting.
Add-on to thiazolidinedione with or without metformin
For the 16-week placebo-controlled study of Byetta add-on to a thiazolidinedione, with or without metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with an incidence of ≥2% and occurring more frequently in Byetta-treated patients compared with placebo-treated patients.
| With a TZD or TZD/MET | Placebo N = 112 % | All Byetta BID N = 121 % |
|---|---|---|
| BID = twice daily. | ||
| ||
| Nausea | 15 | 40 |
| Vomiting | 1 | 13 |
| Dyspepsia | 1 | 7 |
| Diarrhea | 3 | 6 |
| Gastroesophageal Reflux Disease | 0 | 3 |
Adverse reactions reported in ≥1.0 to <2.0% of patients receiving Byetta and reported more frequently than with placebo included decreased appetite. Chills (n = 4) and injection-site reactions (n = 2) occurred only in Byetta-treated patients. The two patients who reported an injection-site reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic hypersensitivity pneumonitis) were reported in the Byetta arm. No serious adverse events were reported in the placebo arm.
The most common adverse reactions leading to withdrawal for Byetta-treated patients were nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to nausea.
Add-on to insulin glargine with or without metformin and/or thiazolidinedione
For the 30-week placebo-controlled study of Byetta as add-on to insulin glargine with or without oral antihyperglycemic medications, Table 5 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in Byetta-treated patients compared with placebo-treated patients.
| With Insulin Glargine | Placebo N = 122 % | All Byetta BID N = 137 % |
|---|---|---|
| BID = twice daily. | ||
| ||
| Nausea | 8 | 41 |
| Vomiting | 4 | 18 |
| Diarrhea | 8 | 18 |
| Headache | 4 | 14 |
| Constipation | 2 | 10 |
| Dyspepsia | 2 | 7 |
| Asthenia | 1 | 5 |
| Abdominal Distention | 1 | 4 |
| Decreased Appetite | 0 | 3 |
| Flatulence | 1 | 2 |
| Gastroesophageal Reflux Disease | 1 | 2 |
The most frequently reported adverse reactions leading to withdrawal for Byetta-treated patients were nausea (5.1%) and vomiting (2.9%). No placebo-treated patients withdrew due to nausea or vomiting.
Post-Marketing Experience
The following additional adverse reactions have been reported during post-approval use of Byetta. 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 [see Warnings and Precautions (5.6)].
Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding [see Drug Interactions (7.2)].
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 [see Limitations of Use (1.2) and Warnings and Precautions (5.1)].
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 [see Warnings and Precautions (5.3)].
Skin and Subcutaneous Tissue Disorders: alopecia
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 [see Adverse Reactions (6.2)]. 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 [see Clinical Pharmacology (12.3)].
Warfarin
There are postmarketing reports of increased INR sometimes associated with bleeding, with concomitant use of warfarin and Byetta [see Adverse Reactions (6.2)]. In a drug interaction study, Byetta did not have a significant effect on INR [see Clinical Pharmacology (12.3)]. In patients taking warfarin, prothrombin time should be monitored more frequently after initiation or alteration of Byetta therapy. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on warfarin.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of Byetta use in pregnant women. In animal studies, exenatide caused cleft palate, irregular skeletal ossification and an increased number of neonatal deaths. Byetta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 had no adverse fetal effects. At the maximal dose, 760 mcg/kg/day, systemic exposures were up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC [see Nonclinical Toxicology (13.3)].
In developmental toxicity studies, pregnant animals received exenatide subcutaneously during organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Moreover, fetuses from pregnant mice given SC doses of 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 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC [see Nonclinical Toxicology (13.3)].
Lactating mice given SC doses of 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 2-4 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 [see Nonclinical Toxicology (13.3)].
Pregnancy Registry
Amylin Pharmaceuticals, Inc. maintains a Pregnancy Registry to monitor pregnancy outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling 1-800-633-9081.
Nursing Mothers
It is not known whether exenatide is excreted in human milk. However, exenatide is present at low concentrations (less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing) in the milk of lactating mice. Many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from exenatide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account these potential risks against the glycemic benefits to the lactating woman. Caution should be exercised when Byetta is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Byetta have not been established in pediatric patients.
Geriatric Use
Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see Clinical Pharmacology (12.3)]. Byetta was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. No differences in safety or effectiveness were observed between these patients and younger patients. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function.
Renal Impairment
Byetta 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. No dosage adjustment of Byetta is required in patients with mild renal impairment (creatinine clearance 50 to 80 mL/min). Caution should be applied when initiating or escalating doses of Byetta from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min) [see Clinical Pharmacology (12.3)].
Hepatic Impairment
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 dysfunction is not expected to affect blood concentrations of exenatide [see Clinical Pharmacology (12.3)].
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 Description
Byetta (exenatide) is a synthetic peptide that was originally identified in the lizard Heloderma suspectum. 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 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 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 - Clinical Pharmacology
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.
Byetta improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.
Pharmacodynamics
Glucose-dependent insulin secretion: Byetta 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 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 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 compared with saline (p <0.001 for both).
Figure 1: Mean (+SEM) Insulin Secretion Rate During Infusion of Byetta 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 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 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.
Postprandial Glucose
In patients with type 2 diabetes, Byetta reduces postprandial plasma glucose concentrations (Figure 2).
Figure 2: Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 of Byettaa Treatment in Patients With Type 2 Diabetes Treated With Metformin, a Sulfonylurea, or Both (N = 54)
Fasting Glucose
In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, immediate insulin release followed injection of Byetta. Plasma glucose concentrations were significantly reduced with Byetta compared with placebo (Figure 3).
Figure 3: Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations Following a One-Time Injection of Byettaa or Placebo in Fasting Patients With Type 2 Diabetes (N = 12)
Cardiac Electrophysiology
The effect of exenatide 10 µg subcutaneously on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover thorough QTc study in 62 healthy subjects. In this study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms. Thus, Byetta (10 mcg single dose) was not associated with clinically meaningful prolongation of the QTc interval.
Pharmacokinetics
Absorption
Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 h. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC0-inf) was 1036 pg∙h/mL following SC administration of a 10-mcg dose of Byetta. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 mcg to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of Byetta in the abdomen, thigh, or upper arm.
Distribution
The mean apparent volume of distribution of exenatide following SC administration of a single dose of Byetta is 28.3 L.
Metabolism and Elimination
Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/h and the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 h post-dose.
Drug Interactions
Acetaminophen
When 1000 mg acetaminophen elixir was given with 10 mcg Byetta (0 h) and 1 hour, 2 hours, and 4 hours after Byetta injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively; Tmax was increased from 0.6 hour in the control period to 0.9 hour, 4.2 hours, 3.3 hours, and 1.6 hours, respectively. Acetaminophen AUC, Cmax and Tmax were not significantly changed when acetaminophen was given 1 hour before Byetta injection.
Digoxin
Administration of repeated doses of Byetta (10 mcg BID) 30 minutes before oral digoxin (0.25 mg QD) decreased the Cmax of digoxin by 17% and delayed the Tmax of digoxin by approximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g., AUC) of digoxin was not changed.
Lovastatin
Administration of Byetta (10 mcg BID) 30 minutes before a single oral dose of lovastatin (40 mg) decreased the AUC and Cmax of lovastatin by approximately 40% and 28%, respectively, and delayed the Tmax by about 4 hours compared with lovastatin administered alone. In the 30-week controlled clinical trials of Byetta, the use of Byetta in patients already receiving HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles compared to baseline.
Lisinopril
In patients with mild to moderate hypertension stabilized on lisinopril (5 to 20 mg/day), Byetta (10 mcg BID) did not alter steady-state Cmax or AUC of lisinopril. Lisinopril steady-state Tmax was delayed by 2 hours. There were no changes in 24-h mean systolic and diastolic blood pressure.
Oral Contraceptives
The effect of Byetta (10 mcg BID) on single and on multiple doses of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied in healthy female subjects. Repeated daily doses of the oral contraceptive (OC) given 30 minutes after Byetta administration decreased the Cmax of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively and delayed the Tmax of ethinyl estradiol and levonorgestrel by 3.0 hours and 3.5 hours, respectively, as compared to the oral contraceptive administered alone. Administration of repeated daily doses of the OC one hour prior to Byetta administration decreased the mean Cmax of ethinyl estradiol by 15% but the mean Cmax of levonorgestrel was not significantly changed as compared to when the OC was given alone. Byetta did not alter the mean trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens. However, the mean trough concentration of ethinyl estradiol was increased by 20% when the OC was administered 30 minutes after Byetta administration injection as compared to when the OC was given alone. The effect of Byetta on OC pharmacokinetics is confounded by the possible food effect on OC in this study. Therefore, OC products should be administered at least one hour prior to Byetta injection.
Warfarin
Administration of warfarin (25 mg) 35 minutes after repeated doses of Byetta (5 mcg BID on days 1-2 and 10 mcg BID on days 3-9) in healthy volunteers delayed warfarin Tmax by approximately 2 hours. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of warfarin were observed. Byetta did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of warfarin [see Drug Interactions (7.2)].
Specific Populations
Renal Impairme
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