Byetta

Exenatide is an injectable drug that reduces the level of sugar (glucose) in the blood. It is used for treating type 2 diabetes. Exenatide belongs in a class of drugs called incretin mimetics because these drugs mimic the effects of incretins. Incretins, such as human-glucagon-like peptide-1 (GLP-1), are hormones that are produced and released into the blood by the intestine in response to food. GLP-1 increases the secretion of insulin from the pancreas, slows absorption of glucose from the gut, and reduces the action of glucagon. (Glucagon is a hormone that increases glucose production by the liver.) All three of these actions reduce levels of glucose in the blood. In addition, GLP-1 reduces appetite. Exenatide is a synthetic (man-made) hormone that resembles and acts like GLP-1. In studies, exenatide-treated patients achieved lower blood glucose levels and experienced weight loss. Exenatide was approved by the FDA in May 2005.

GENERIC AVAILABLE: No.

Exenatide slows down transit of food and drugs through the intestine and, therefore, can reduce the absorption of drugs that are taken orally. To avoid this interaction, administer oral medications one hour before exenatide is administered. Orally administered drugs that need to be administered with food should be given with a light meal or snack when exenatide is not administered.

There are no adequate studies of exenatide in pregnant women. Most experts agree that insulin is the drug of choice in pregnant women with diabetes.

There are no adequate studies of exenatide in nursing mothers, and it is not known whether exenatide is excreted in human breast milk.

It is not known if Byetta crosses into human milk.

Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Byetta.

Take Byetta exactly as prescribed

Byetta comes in a prefilled pen injection to be given directly under the skin. 

Your healthcare provider must teach you how to inject Byetta before you use it for the first time. If you have questions or do not understand the instructions, talk to your healthcare provider or pharmacist.

• Inject your dose of Byetta under the skin (subcutaneous injection) of your upper leg (thigh), stomach area (abdomen), or upper arm as instructed by your healthcare provider. Do not inject into a vein or muscle.
• Byetta is injected two times each day, at any time within the 60 minutes (1 hour) before your morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Do not take Byetta after your meal.
• If you miss a dose, skip that dose and take your next dose at the next prescribed time. Do not take an extra dose or increase the amount of your next dose to make up for a missed dose.
• If you use too much Byetta, call your healthcare provider or poison control center right away. Too much Byetta can cause your blood sugar to drop quickly and you may have symptoms of low blood sugar. You may need medical treatment right away. Too much Byetta can also cause severe nausea and vomiting.

Follow your healthcare provider's instructions for diet, exercise, and how often to test your blood sugar. If you see your blood sugar increasing during treatment with Byetta, talk to your healthcare provider because you may need to adjust your current treatment plan for your diabetes.

Talk to your healthcare provider about how to manage high blood sugar (hyperglycemia) and low blood sugar (hypoglycemia), and how to recognize problems that can happen with your diabetes.

Never share your Byetta with another person. You may give an infection to them, or get an infection from them, and Byetta may harm them.

Byetta Pen

• Store your new, unused Byetta pen in the original carton in a refrigerator at 36 °F to 46 °F (2 °C to 8 °C).
• After first use, keep your pen at a temperature cooler than 77 °F (25 °C). Do not freeze.
• Protect Byetta from light.
• Use a Byetta pen for only 30 days. Throw away a used pen after 30 days, even if there is some medicine left in the pen.
• Do not use Byetta after the expiration date printed on the label.
• Do not store the Byetta pen with the needle attached. If the needle is left on, medicine may leak from the pen or air bubbles may form in the cartridge.
• Keep your Byetta pen, pen needles, and all medicines out of the reach of children.

Byetta Trays

• Store Byetta in the refrigerator at 36°F to 46°F (2°C to 8°C).
• Do not use Byetta past the expiration date. The expiration date is labeled EXP and can be found on the paper cover of the single-dose tray.
• Do not freeze Byetta trays. Do not use Byetta if it has been frozen.
• Protect Byetta from light until you are ready to prepare and use your dose.
• If needed, you can keep your Byetta tray out of the refrigerator at 68°F to 77°F (20°C to 25°C) for up to 4 weeks.
• See the Instructions for Use for information about how to throw away your used Byetta parts.
• Keep this and all medications out of the reach of children.

Antidiabetic agent; synthetic, human glucagon-like peptide-1 (GLP-1) receptor agonist (incretin mimetic).1 2 3 4 38

GI Absorption of Other Drugs

Possible decreased rate and extent of absorption of concomitantly administered oral drugs; use caution with oral drugs that have a narrow therapeutic index or require rapid GI absorption.1 38

With oral drugs for which efficacy depends on threshold concentrations, administer ≥1 hour before exenatide.1 9 If such drugs need to be administered with food, administer them with a meal or snack (e.g., lunch) at a time when exenatide is not administered.1

Specific Drugs

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Weight loss.
• Hard stools (constipation).
• Loose stools (diarrhea).
• Not hungry.
• Upset stomach or throwing up.
• Feeling tired or weak.
• Itching where the shot is given.
• Small bump where the shot is given.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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.

Table 1 summarizes the incidence and rate of hypoglycemia with Byetta in six placebo-controlled clinical trials.

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 (5.6)].

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 (5.6)].

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 (5.6)].

Antibodies to exenatide were not assessed in the 30-week placebo-controlled trial of Byetta used in combination with insulin glargine.

In the 30-week comparator-controlled trial of Byetta used in combination with insulin glargine and metformin, 60 patients (20%) had low titer antibodies to exenatide at 30 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 234 patients (77%) without antibody titers. An additional 10 patients (3%) had higher titer antibodies at 30 weeks. Of these patients, 2 (1% overall) had an attenuated glycemic response to Byetta; the remaining 8 (3% overall) had a glycemic response comparable to that of patients without antibodies [see Warnings and Precautions (5.5)].

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.

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.

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

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 (5.3)] are summarized in Table 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.

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.

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.

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.

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.

Postmarketing Experience

The following additional adverse reactions have been reported during postapproval 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 (5.7)].

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 Indications and Usage (1.2) and Warnings and Precautions (5.2)].

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 (5.4)].

Skin and Subcutaneous Tissue Disorders: alopecia

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) 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).

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

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.

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

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.

Byetta slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.

In both animals and humans, administration of exenatide has been shown to reduce food intake.

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)

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)

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 msec. Thus, Byetta (10 mcg single dose) was not associated with clinically meaningful prolongation of the QTc interval.

Pharmacokinetics

Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 hours. 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 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.

The mean apparent volume of distribution of exenatide following SC administration of a single dose of Byetta is 28.3 L.

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/hour and the mean terminal half-life is 2.4 hours. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 hours post-dose.

Acetaminophen

When 1000 mg acetaminophen elixir was given with 10 mcg Byetta (0 hour) 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 once daily) 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 (5-20 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-hour 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)].

Renal Impairment

Pharmacokinetics of exenatide was studied in subjects with normal, mild, or moderate renal impairment and subjects with end-stage renal disease. In subjects with mild to moderate renal impairment (creatinine clearance 30-80 mL/min), exenatide exposure was similar to that of subjects with normal renal function. However, in subjects with end-stage renal disease receiving dialysis, mean exenatide exposure increased by 3.37-fold compared to that of subjects with normal renal function [see Use in Specific Populations (8.6)].

Hepatic Impairment

No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment [see Use in Specific Populations (8.7)].

Age

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 Use in Specific Population (8.5)].

Gender

Population pharmacokinetic analysis of male and female patients suggests that gender does not influence the distribution and elimination of exenatide.

Race

Population pharmacokinetic analysis of samples from Caucasian, Hispanic, Asian, and Black patients suggests that race has no significant influence on the pharmacokinetics of exenatide.

Body Mass Index

Population pharmacokinetic analysis of patients with body mass indices (BMI) ≥30 kg/m2 and <30 kg/m2 suggests that BMI has no significant effect on the pharmacokinetics of exenatide.