Exenatide Injection

Name: Exenatide Injection

What other information should I know?

Your blood sugar and glycosylated hemoglobin (HbA1c) should be checked regularly to determine your response to exenatide. Your doctor will also tell you how to check your response to this medication by measuring your blood or urine sugar levels at home. Follow these instructions carefully.

Do not let anyone else use your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

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 (exenatide injection) 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).

Indications

Type 2 Diabetes Mellitus

BYETTA (exenatide injection) 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 (exenatide injection) is not a substitute for insulin. BYETTA (exenatide injection) should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

The concurrent use of BYETTA (exenatide injection) with insulin has not been studied and cannot be recommended.

Based on postmarketing data BYETTA (exenatide injection) has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. BYETTA (exenatide injection) 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 injection) . Other antidiabetic therapies should be considered in patients with a history of pancreatitis.

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 (exenatide injection) 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. Exenatide promotes insulin release from pancreatic beta cells in the presence of elevated glucose concentrations.

BYETTA (exenatide injection) 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 injection) 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 injection) 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 injection) 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 injection) compared with saline (p < 0.001 for both).

Figure 1: Mean (+SEM) Insulin Secretion Rate During Infusion of BYETTA (exenatide injection) 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 injection) 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 injection) 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.

Pharmacodynamics

Postprandial Glucose

In patients with type 2 diabetes, BYETTA (exenatide injection) reduces postprandial plasma glucose concentrations (Figure 2).

Figure 2: Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 of BYETTA (exenatide injection) a 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 (exenatide injection) . Plasma glucose concentrations were significantly reduced with BYETTA (exenatide injection) compared with placebo (Figure 3).

Figure 3: Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations Following a One-Time Injection of BYETTA (exenatide injection) a or Placebo in Fasting Patients With Type 2 Diabetes (N = 12)

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 (exenatide injection) 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 (exenatide injection) 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 (exenatide injection) (0 h) and 1 hour, 2 hours, and 4 hours after BYETTA (exenatide injection) 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 (exenatide injection) injection.

Digoxin

Administration of repeated doses of BYETTA (exenatide injection) (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 (exenatide injection) (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 (exenatide injection) , the use of BYETTA (exenatide injection) 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 (exenatide injection) (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 (exenatide injection) (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 (exenatide injection) 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 (exenatide injection) 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 (exenatide injection) 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 (exenatide injection) administration injection as compared to when the OC was given alone. The effect of BYETTA (exenatide injection) 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 (exenatide injection) injection.

Warfarin

Administration of warfarin (25 mg) 35 minutes after repeated doses of BYETTA (exenatide injection) (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 (exenatide injection) did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of warfarin [see DRUG INTERACTIONS].

Specific Populations

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 to 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].

Hepatic Impairment

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

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].

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.

Clinical Studies

BYETTA (exenatide injection) has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione.

Monotherapy

In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, BYETTA (exenatide injection) 5 mcg BID (n = 77), BYETTA (exenatide injection) 10 mcg BID (n = 78), or placebo BID (n = 77) was used as monotherapy in patients with entry HbA1c ranging from 6.5-10%. All patients assigned to BYETTA (exenatide injection) initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA (exenatide injection) 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. BYETTA (exenatide injection) 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 HbA1c from baseline to Week 24 (or the last value at time of early discontinuation). Compared to placebo, BYETTA (exenatide injection) 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in HbA1c from baseline at Week 24 (Table 5).

Table 5: Results of 24-Week Placebo-Controlled Trial of BYETTA (exenatide injection) Used as Monotherapy

  Placebo BID BYETTA 5 mcg BID BYETTA 10 mcg* BID
Intent-to-Treat Population (N) 77 77 78
HbA1c (%), Mean
  Baseline 7.8 7.9 7.8
  Change at Week 24† -0.2 -0.7 -0.9
  Difference from placebo†(95% CI)   -0.5 [-0.9, -0.2]‡ -0.7 [-1.0, -0.3]‡
Proportion Achieving HbA1c < 7% 38% 48% 53%
Body Weight (kg), Mean
  Baseline 86.1 85.1 86.2
  Change at Week 24† -1.5 -2.7 -2.9
  Difference from placebo†(95% CI)   -1.3 [-2.3, -0.2] -1.5 [-2.5, -0.4]
Fasting Serum Glucose§ (mg/dL), Mean
  Baseline 159 166 155
  Change at Week 24† -5 -17 -19
  Difference from placebo† (95% CI)   -12 [-23.2, -1.3] -14 [-24.5, -2.5]
* BYETTA (exenatide injection) 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 5 months before the morning and evening meals.
† Least squares means are adjusted for screening HbA1c strata and baseline value of the dependent variable.
‡ p < 0.01, treatment vs. placebo.
§ Measured using the hexokinase-based glucose method.
BID = twice daily.

On average, there were no adverse effects of exenatide on blood pressure or lipids.

Combination Therapy

Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of BYETTA (exenatide injection) 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 injection) 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 injection) 5 mcg BID, BYETTA (exenatide injection) 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 injection) initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA (exenatide injection) 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 HbA1c values at baseline for the trials ranged from 8.2% to 8.7%.

In the placebo-controlled trial of 16 weeks duration, BYETTA (exenatide injection) (n = 121) or placebo (n = 112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin. Randomization to BYETTA (exenatide injection) or placebo was stratified based on whether the patients were receiving metformin. BYETTA (exenatide injection) 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 injection) 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 HbA1c values were 7.9% for BYETTA (exenatide injection) and placebo.

The primary endpoint in each study was the mean change in HbA1c from baseline to study end (or early discontinuation). Table 6 summarizes the study results for the 30-week and 16-week clinical trials.

Table 6: Results of 30-Week and 16-Week Placebo-Controlled Trials of BYETTA (exenatide injection) Used in Combination with Oral Antidiabetic Agents

  Placebo BID BYETTA 5 mcg BID BYETTA 10 mcg* BID
In Combination With Metformin (30 Weeks)
Intent-to-Treat Population (N) 113 110 113
HbA1c (%), Mean
  Baseline 8.2 8.3 8.2
  Change at Week 30† -0.0 -0.5 -0.9
  Difference from placebo† (95% CI)   -0.5 [-0.7, -0.2]‡ -0.9 [-1.1, -0.6]‡
Proportion Achieving HbA 1c

Patient information

Medication Guide

BYETTA®
(bye-A-tuh)
(exenatide) Injection

Read this Medication Guide and the Pen User Manual that come with BYETTA before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have questions about BYETTA after reading this information, ask your healthcare provider or pharmacist.

What is the most important information I should know about BYETTA?

Serious side effects can happen in people who take BYETTA, including inflammation of the pancreas (pancreatitis) which may be severe and lead to death.

Before taking BYETTA, tell your healthcare provider if you have had:

  • pancreatitis.
  • stones in your gallbladder (gallstones).
  • a history of alcoholism.
  • high blood triglyceride levels.

These medical conditions can make you more likely to get pancreatitis in general. It is not known if having these conditions will lead to a higher chance of getting pancreatitis while taking BYETTA.

While taking BYETTA:

Call your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe, and will not go away. The pain may happen with or without vomiting. The pain may be felt going from your abdomen through to your back. These may be symptoms of pancreatitis.

What is BYETTA?

  • BYETTA is an injectable prescription medicine that may improve blood sugar (glucose) control in adults with type 2 diabetes mellitus, when used with a diet and exercise program.
  • BYETTA is not insulin.
  • You should not take BYETTA instead of insulin.
  • The use of BYETTA with short acting insulin is not recommended.
  • The use of BYETTA with rapid acting insulin is not recommended.
  • BYETTA is not for people with type 1 diabetes or people with diabetic ketoacidosis.
  • It is not known if BYETTA is safe and effective in children.
  • BYETTA has not been studied in people who have pancreatitis.
  • BYETTA should not be used in people who have severe kidney problems.

Who should not use BYETTA?

Do not use BYETTA if:

  • you have had an allergic reaction to exenatide or any of the other ingredients in BYETTA. See the end of this Medication Guide for a complete list of ingredients in BYETTA.

Symptoms of a severe allergic reaction with BYETTA may include:

  • swelling of your face, lips, tongue, or throat
  • problems breathing or swallowing
  • severe rash or itching
  • fainting or feeling dizzy
  • very rapid heartbeat

What should I tell my healthcare provider before using BYETTA?

Before taking BYETTA, tell your healthcare provider if you:

  • have or have had pancreatitis, stones in your gallbladder (gallstones), a history of alcoholism, or high blood triglyceride levels.
  • have severe problems with your stomach, such as delayed emptying of your stomach (gastroparesis) or problems with digesting food.
  • have or have had kidney problems, or have had a kidney transplant.
  • have any other medical conditions.
  • are pregnant or plan to become pregnant. It is not known if BYETTA will harm your unborn baby.
    Pregnancy Registry: Amylin Pharmaceuticals, Inc. has a registry for women who take BYETTA during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. If you take BYETTA at any time during pregnancy you may enroll in this registry by calling (800) 6339081.
  • are breastfeeding or plan to breast-feed. It is not known if BYETTA passes into your breast milk. You and your healthcare provider should decide if you will take BYETTA or breast-feed. You should not do both without talking with your healthcare provider first.

Tell your healthcare provider about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. BYETTA slows stomach emptying and can affect medicines that need to pass through the stomach quickly. BYETTA may affect the way some medicines work and some other medicines may affect the way BYETTA works.

Especially tell your healthcare provider if you take:

  • Other anti-diabetes medicines, especially sulfonylurea medicines or insulin.
  • birth control pills that are taken by mouth (oral contraceptives). BYETTA may lower the amount of the medicine in your blood from your birth control pills and they may not work as well to prevent pregnancy. Take your birth control pills at least one hour before your injection of BYETTA. If you must take your birth control pills with food, take it with a meal or snack where you do not also take BYETTA.
  • an antibiotic. Take antibiotic medicines at least one hour before taking BYETTA. If you must take your antibiotic with food, take it with a meal or snack where you do not also take BYETTA.
  • warfarin sodium (Coumadin®, Jantoven®).
  • a blood pressure medicine.
  • a water pill (diuretic).
  • a pain medicine.
  • lovastatin (Altoprev®, Mevacor®, Advicor®).

Ask your healthcare provider if you are not sure if your medicine is listed above.

Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist each time you get a new medicine.

How should I use BYETTA?

See the Pen User Manual that comes with BYETTA for instructions for using the BYETTA Pen and injecting BYETTA.

  • Your healthcare provider may prescribe BYETTA alone or with certain other medicines to help control your blood sugar.
  • BYETTA comes in a prefilled pen.
  • Use BYETTA exactly as prescribed by your healthcare provider. Do not change your dose unless your healthcare provider has told you to change your dose.
  • 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.
  • Pen needles are not included. You may need a prescription to purchase pen needles from your pharmacist. Ask your healthcare provider which needle length and gauge is best for you.
  • 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.
  • Do not mix BYETTA and insulin in the same syringe or vial even if you take them at the same time.
  • 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 of BYETTA, 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 pen with another person. You may give an infection to them, or get an infection from them, and BYETTA may harm them.

What are the possible side effects of BYETTA?

BYETTA can cause serious side effects.

See “What is the most important information I should know about BYETTA?”

It is not known whether BYETTA, or other anti-diabetes medications, increase your risk of a heart attack or stroke.

  • Low blood sugar (hypoglycemia). Your risk for getting low blood sugar is higher if you take BYETTA with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. The dose of your sulfonylurea or insulin medicine may need to be lowered while you use BYETTA. Signs and symptoms of low blood sugar may include:

  • headache
  • drowsiness
  • weakness
  • dizziness
  • confusion
  • irritability
  • hunger
  • fast heart beat
  • sweating
  • feeling jittery

Talk with your healthcare provider about how to treat low blood sugar.

  • Kidney problems. BYETTA may cause new or worse problems with kidney function, including kidney failure. Dialysis or kidney transplant may be needed.
    • While taking BYETTA:
      Call your healthcare provider right away if you have nausea, vomiting, or diarrhea that will not go away, or if you cannot take liquids by mouth. You may be at increased risk for kidney problems.
  • Severe allergic reactions. Severe allergic reactions can happen with BYETTA. Stop taking BYETTA, and get medical help right away if you have any symptom of a severe allergic reaction. See “Who should not take BYETTA?”

The most common side effects with BYETTA include:

  • nausea. Nausea most commonly happens when first starting BYETTA, but may become less over time.
  • vomiting.
  • diarrhea.
  • feeling jittery.
  • dizziness.
  • headache.
  • acid stomach.
  • constipation.
  • weakness.

Talk to your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the side effects with BYETTA.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store BYETTA?

  • 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 BYETTA Pen at a temperature cooler than 77°F (25°C).
  • Do not freeze your BYETTA Pen. Do not use BYETTA if it has been frozen.
  • Protect BYETTA from light.
  • Use a BYETTA Pen for only 30 days. Throw away a used BYETTA 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 BYETTA Pen or air bubbles may form in the cartridge.
  • See the BYETTA Pen User Manual for instructions about the right way to throw away your BYETTA Pen.
  • Keep your BYETTA Pen, pen needles, and all medicines out of the reach of children.

General information about BYETTA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BYETTA for a condition for which it was not prescribed. Do not give BYETTA to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide includes the most important information you should know about using BYETTA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about BYETTA that is written for health professionals.

For more information about BYETTA, go to http://www.BYETTA.com or call BYETTA Customer Service at 1-800-868-1190.

What are the ingredients in BYETTA?

Active Ingredient: exenatide

Inactive Ingredients: metacresol, mannitol, glacial acetic acid, and sodium acetate trihydrate in water for injection.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

What is byetta (byetta prefilled pen)?

Exenatide is an injectable diabetes medicine that helps control blood sugar levels. This medication helps your pancreas produce insulin more efficiently. Byetta is a short-acting form of exenatide.

Exenatide is used to treat type 2 diabetes. Other diabetes medicines are sometimes used in combination with exenatide if needed.

This medication guide provides information about the Byetta brand of exenatide. Bydureon is another brand of exenatide that is not covered in this medication guide.

Exenatide may also be used for purposes not listed in this medication guide.

Side effects

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 (exenatide injection) in five placebo-controlled clinical trials.

Table 1: Incidence (%) and Rate of Hypoglycemia When BYETTA (exenatide injection) was Used as Monotherapy or With Concomitant Antidiabetic Therapy in Five Placebo-Controlled Clinical Trials*

  BYETTA
Placebo twice daily 5 mcg twice daily 10 mcg twice daily
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 Dose not studied 121
% Overall 7.1% Dose not studied 10.7%
Rate(episodes/patient-years) 0.56 Dose not studied 0.98
% Severe 0.0% Dose not studied 0.0%
* For the 30-week trials, a hypoglycemia episode was recorded if the patient reported symptoms consistent with hypoglycemia and was recorded as severe if the subject required the assistance of another person to treat the event. For the other trials, a hypoglycemic episode was recorded if a patient reported signs or symptoms of hypoglycemia or had a blood glucose value consistent with hypoglycemia regardless of associated symptoms or treatment and was recorded as severe if the subject required the assistance of another person to treat the event. The requirement for assistance had to be accompanied by a blood glucose measurement of < 50 mg/dL or prompt recovery after administration of oral carbohydrate.
N = The number of Intent-to-Treat subjects in each treatment group.

Immunogenicity

In the 30-week controlled trials of BYETTA (exenatide injection) add-on to metformin and/or sulfonylurea, 38% of patients had low titer antibodies to exenatide at 30 weeks. For this group, the level of glycemic control (hemoglobin A1c [HbA1c]) was generally comparable to that observed in those without antibody titers. An additional 6% of patients had higher titer antibodies at 30 weeks. In about half of this 6% (3% of the total patients given BYETTA (exenatide injection) in the 30-week controlled studies), the glycemic response to BYETTA (exenatide injection) was attenuated; the remainder had a glycemic response comparable to that of patients without antibodies.

In the 16-week trial of BYETTA (exenatide injection) add-on to thiazolidinediones, with or without metformin, 9% of patients had higher titer antibodies at 16 weeks. In the 24-week trial of BYETTA (exenatide injection) used as monotherapy, 3% of patients had higher titer antibodies at 24 weeks. Compared with patients who did not develop antibodies to BYETTA (exenatide injection) , on average the glycemic response in patients with higher titer antibodies was attenuated [see WARNINGS AND PRECAUTIONS].

Other Adverse Reactions

Monotherapy

For the 24-week placebo-controlled study of BYETTA (exenatide injection) used as a monotherapy, Table 2 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥ 2% and occurring more frequently in BYETTA (exenatide injection) -treated patients compared with placebo-treated patients.

Table 2: Treatment-Emergent Adverse Reactions ≥ 2% Incidence With BYETTA (exenatide injection) Used as Monotherapy (Excluding Hypoglycemia)*

Monotherapy Placebo BID
N = 77
%		 All BYETTA (exenatide injection) BID
N = 155
%
Nausea 0 8
Vomiting 0 4
Dyspepsia 0 3
* In a 24-week placebo-controlled trial.
BID = twice daily.

Adverse reactions reported in ≥ 1.0 to < 2.0% of patients receiving BYETTA (exenatide injection) and reported more frequently than with placebo included decreased appetite, diarrhea, and dizziness. The most frequently reported adverse reaction associated with BYETTA (exenatide injection) , nausea, occurred in a dose-dependent fashion.

Two of the 155 patients treated with BYETTA (exenatide injection) 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 (exenatide injection) add-on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence ≥ 2% and occurring more frequently in BYETTA (exenatide injection) -treated patients compared with placebo-treated patients [see WARNINGS AND PRECAUTIONS] are summarized in Table 3.

Table 3: Treatment-Emergent Adverse Reactions ≥ 2% Incidence and Greater Incidence With BYETTA (exenatide injection) Treatment Used With Metformin and/or a Sulfonylurea (Excluding Hypoglycemia)*

  Placebo BID
N = 483
%		 All BYETTA (exenatide injection) BID
N = 963
%
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
* In three 30-week placebo-controlled clinical trials.
BID = twice daily.

Adverse reactions reported in ≥ 1.0 to < 2.0% of patients receiving BYETTA (exenatide injection) 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 (exenatide injection) -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 (exenatide injection) 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 (exenatide injection) -treated patients compared with placebo-treated patients.

Table 4: Treatment-Emergent Adverse Reactions ≥ 2% Incidence With BYETTA (exenatide injection) Used With a Thiazolidinedione, With or Without Metformin (Excluding Hypoglycemia)*

With a TZD or TZD/MET Placebo
N = 112
%		 All BYETTA (exenatide injection) BID
N = 121
%
Nausea 15 40
Vomiting 1 13
Dyspepsia 1 7
Diarrhea 3 6
Gastroesophageal Reflux Disease 0 3
* In a 16-week placebo-controlled clinical trial.
BID = twice daily.

Adverse reactions reported in ≥ 1.0 to < 2.0% of patients receiving BYETTA (exenatide injection) and reported more frequently than with placebo included decreased appetite. Chills (n = 4) and injection-site reactions (n = 2) occurred only in BYETTA (exenatide injection) -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 (exenatide injection) arm. No serious adverse events were reported in the placebo arm.

The most common adverse reactions leading to withdrawal for BYETTA (exenatide injection) -treated patients were nausea (9%) and vomiting (5%). For placebo-treated patients, < 1% withdrew due to nausea.

Post-Marketing Experience

The following additional adverse reactions have been reported during post-approval use of BYETTA (exenatide injection) . 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].

Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding [see DRUG INTERACTIONS].

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 and WARNINGS AND PRECAUTIONS].

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].

Skin and Subcutaneous Tissue Disorders: alopecia

Read the entire FDA prescribing information for Byetta (Exenatide Injection)

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What are some things I need to know or do while I take Exenatide Injection?

  • Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how exenatide injection affects you.
  • Wear disease medical alert ID (identification).
  • Do not drive if your blood sugar has been low. There is a greater chance of you having a crash.
  • Check your blood sugar as you have been told by your doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • If you are taking warfarin, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with this medicine.
  • It may be harder to control your blood sugar during times of stress like when you have a fever, an infection, an injury, or surgery. A change in level of physical activity or exercise and a change in diet may also affect your blood sugar. Talk with your doctor.
  • Talk with your doctor before you drink alcohol.
  • A very bad and sometimes deadly pancreas problem (pancreatitis) has happened with exenatide injection. Talk with your doctor.
  • Do not share with another person even if the needle has been changed. Sharing your tray or pen may pass infections from one person to another. This includes infections you may not know you have.
  • If you are 65 or older, use this medicine with care. You could have more side effects.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using exenatide injection while you are pregnant.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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