Exenatide

# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider.  WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery.  The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements.  WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

# Overview
Exenatide is a GLP-1 receptor agonist that is FDA approved for the treatment of type 2 diabetes mellitus.   Common adverse reactions include injection site mass, injection site pruritus, injection site reaction, hypoglycemia, constipation, diarrhea, indigestion, nausea, vomiting, antibody development, asthenia, dizziness, nervousness, headache.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Type 2 Diabetes Mellitus
- Dosing information
- 5 mg injection SC bid 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)
- Exenatide should not be administered after a meal.
- Based on clinical response, the dose of Exenatide can be increased to 10 mcg SC injection bid 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 Exenatide with insulin. Do not transfer Exenatide from the pen to a syringe or a vial. No data are available on the safety or efficacy of intravenous or intramuscular injection of Exenatide.

### Important limitations of use
- Exenatide is not a substitute for insulin. Exenatide should not be used for the treatment of type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.
- The concurrent use of Exenatide with prandial insulin has not been studied and cannot be recommended.
- Based on post marketing data Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Exenatide has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Exenatide. Other anti diabetic therapies should be considered in patients with a history of pancreatitis.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of exenatide in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of exenatide in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of Exenatide have not been established in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of exenatide in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of exenatide in pediatric patients.

# Contraindications

### Hypersensitivity
Exenatide is contraindicated in patients with prior severe hypersensitivity reactions to exenatide or to any of the product components.

# Warnings

### Never Share a Exenatide Pen between Patients
Exenatide pens should never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.

### Acute Pancreatitis
- Based on post marketing data, Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis.
- After initiation of Exenatide, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting).
- If pancreatitis is suspected, Exenatide should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Exenatide should not be restarted.
- Consider anti diabetic therapies other than Exenatide in patients with a history of pancreatitis.

### Use with Medications Known to Cause Hypoglycemia
- The risk of hypoglycemia is increased when Exenatide is used in combination with a sulfonylurea. Therefore, patients receiving Exenatide and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia.
- When Exenatide is used in combination with insulin, the dose of insulin should be evaluated. In patients at increased risk of hypoglycemia consider reducing the dose of insulin.
- The concurrent use of Exenatide with prandial  insulin has not been studied and cannot be recommended. It is also possible that the use of Exenatide with other glucose-independent insulin  secretagogues (e.g., meglitinides) could increase the risk of hypoglycemia.

### Renal Impairment
- Exenatide 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 .
- In patients with end-stage renal disease receiving dialysis, single doses of Exenatide 5 mcg were not well tolerated due to gastrointestinal side effects.
- Because Exenatide may induce nausea and vomiting with transient hypovolemia, treatment may worsen renal function. Caution should be applied when initiating or escalating doses of Exenatide from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min).
- There have been post marketing 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 Exenatide.
- Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.

### Gastrointestinal Disease
- Exenatide has not been studied in patients with severe gastrointestinal disease, including gastroparesis.
- Because Exenatide is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea, the use of Exenatide is not recommended in patients with severe gastrointestinal disease.

### Immunogenicity
- Patients may develop antibodies to exenatide following treatment with Exenatide.
- Antibody levels were measured in 90% of subjects in the 30-week, 24-week, and 16-week studies of Exenatide.
- 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 anti diabetic therapy should be considered.

### Hypersensitivity
- There have been post marketing reports of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) in patients treated with Exenatide.
- If a hypersensitivity reaction occurs, the patient should discontinue Exenatide and other suspect medications and promptly seek medical advice.

### Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Exenatide or any other anti diabetic drug.

# Adverse Reactions

## Clinical Trials 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 Exenatide in six placebo-controlled clinical trials.

### Immunogenicity
- Antibodies were assessed in 90% of subjects in the 30-week, 24-week, and 16-week studies of Exenatide. In the 30-week controlled trials of Exenatide 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 Exenatide; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without antibodies.
- In the 16-week trial of Exenatide 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 Exenatide; the remaining 6 (5% overall) had a glycemic response comparable to that of patients without antibodies.
- In the 24-week trial of Exenatide 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 Exenatide; the remaining 2 (1% overall) had a glycemic response comparable to that of patients without antibodies.
- Antibodies to exenatide were not assessed in the 30-week trial of Exenatide used in combination with insulin glargine.
- Two hundred and ten patients with antibodies to exenatide in the Exenatide 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 Exenatide used as a monotherapy, Table 2 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence 2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients.
Adverse reactions reported in 1.0% to <2.0% of patients receiving Exenatide and reported more frequently than with placebo included decreased appetite, diarrhea, and dizziness. The most frequently reported adverse reaction associated with Exenatide, nausea, occurred in a dose-dependent fashion.
Two of the 155 patients treated with Exenatide 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 Exenatide add-on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence 2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients ] are summarized in Table 3.
Adverse reactions reported in 1.0% to <2.0% of patients receiving Exenatide 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 Exenatide-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 Exenatide 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 Exenatide-treated patients compared with placebo-treated patients.
Adverse reactions reported in 1.0% to <2.0% of patients receiving Exenatide and reported more frequently than with placebo included decreased appetite. Chills (n=4) and injection-site reactions (n=2) occurred only in Exenatide-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 Exenatide arm. No serious adverse events were reported in the placebo arm.
The most common adverse reactions leading to withdrawal for Exenatide-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 Exenatide 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 Exenatide-treated patients compared with placebo-treated patients.
The most frequently reported adverse reactions leading to withdrawal for Exenatide-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 post approval use of Exenatide. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, macular or papular rash, angioedema, anaphylactic reaction .
Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding.
Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death.
Neurologic: dysgeusia; somnolence.
Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant and kidney transplant dysfunction.
Skin and Subcutaneous Tissue Disorders: alopecia.

# Drug Interactions

### Orally Administered Drugs
The effect of Exenatide to slow gastric emptying can reduce the extent and rate of absorption of orally administered drugs. Exenatide should be used with caution in patients receiving oral medications that have narrow therapeutic index or require rapid gastrointestinal absorption . For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before Exenatide injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when Exenatide is not administered .

### Warfarin
There are post marketing reports of increased INR sometimes associated with bleeding, with concomitant use of warfarin and Exenatide . In a drug interaction study, Exenatide did not have a significant effect on INR . In patients taking warfarin, prothrombin time should be monitored more frequently after initiation or alteration of Exenatide 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 (FDA): C
There are no adequate and well-controlled studies of Exenatide use in pregnant women. In animal studies, exenatide caused cleft palate, irregular skeletal ossification and an increased number of neonatal deaths. Exenatide 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.
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.
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 to 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.
Pregnancy Registry
A Pregnancy Registry has been implemented to monitor pregnancy outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling 1-800-633-9081.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Exenatide in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Exenatide during labor and delivery.

### 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 Exenatide is administered to a nursing woman.

### Pediatric Use
Safety and effectiveness of Exenatide have not been established in pediatric patients.

### Geriatic 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. Exenatide 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.

### Gender
There is no FDA guidance on the use of Exenatide with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Exenatide with respect to specific racial populations.

### Renal Impairment
Exenatide 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 Exenatide is required in patients with mild renal impairment (creatinine clearance 50-80 mL/min). Caution should be applied when initiating or escalating doses of Exenatide from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min)

### 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 eventide.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Exenatide in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Exenatide in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Injection SC

### Monitoring
FDA package insert for abcixmab contains no information regarding drug monitoring.

# IV Compatibility
There is limited information about the IV compatibility.

# Overdosage
In a clinical study of Exenatide, three patients with type 2 diabetes each experienced a single overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations. One of the three patients experienced severe hypoglycemia requiring parenteral glucose administration. The three patients recovered without complication. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

# Pharmacology

## Mechanism of Action
Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other anti hyperglycemic actions following their release into the circulation from the gut. Exenatide is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.
The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways.
Exenatide improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.

## Structure
Exenatide (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
Exenatide is supplied for SC injection as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID).

## Pharmacodynamics
Glucose-Dependent Insulin Secretion
Exenatide has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. However, Exenatide does not impair the normal glucagon response to hypoglycemia.
First-Phase Insulin Response
In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of Exenatide at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with Exenatide compared with saline (p<0.001 for both).
Glucagon Secretion
In patients with type 2 diabetes, Exenatide moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand.
Gastric Emptying
Exenatide slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.
Food Intake
In both animals and humans, administration of exenatide has been shown to reduce food intake.
Postprandial Glucose
In patients with type 2 diabetes, Exenatide reduces postprandial plasma glucose concentrations (Figure 2).
Fasting Glucose
In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, immediate insulin release followed injection of Exenatide. Plasma glucose concentrations were significantly reduced with Exenatide compared with placebo (Figure 3).
Cardiac Electrophysiology
The effect of exenatide 10 g 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, Exenatide (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 hours. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC0-inf) was 1036 pgh/mL following SC administration of a 10-mcg dose of Exenatide. 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 Exenatide in the abdomen, thigh, or upper arm.
Distribution
The mean apparent volume of distribution of exenatide following SC administration of a single dose of Exenatide 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/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.
Drug Interactions
Acetaminophen
When 1000 mg acetaminophen elixir was given with 10 mcg Exenatide (0 hour) and 1 hour, 2 hours, and 4 hours after Exenatide 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 Exenatide injection.
Digoxin
Administration of repeated doses of Exenatide (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 Exenatide (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 Exenatide, the use of Exenatide 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), Exenatide (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 Exenatide (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 Exenatide 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 Exenatide 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. Exenatide 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 Exenatide administration injection as compared to when the OC was given alone. The effect of Exenatide 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 Exenatide injection.
warfarin
Administration of warfarin (25 mg) 35 minutes after repeated doses of Exenatide (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. Exenatide did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of warfarin .
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 30-80 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.
Hepatic Impairment
No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment.
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 .
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.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
A 104-week carcinogenicity study was conducted in male and female rats at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection. Benign thyroid C-cell adenomas were observed in female rats at all exenatide doses. The incidences in female rats were 8% and 5% in the two control groups and 14%, 11%, and 23% in the low-, medium-, and high-dose groups with systemic exposures of 5, 22, and 130 times, respectively, the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on plasma area under the curve (AUC).
In a 104-week carcinogenicity study in mice at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 95 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay.
In mouse fertility studies with SC doses of 6, 68, or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating, and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

### Reproductive and Developmental Toxicology
In female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7, there were no adverse fetal effects at doses up to 760 mcg/kg/day, systemic exposures up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 (organogenesis), cleft palate (some with holes) and irregular fetal skeletal ossification of rib and skull bones were observed at 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 (organogenesis), irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a systemic exposure 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths was observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

# Clinical Studies
Exenatide has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, a combination of  metformin and a thiazolidinedione, or in combination with insulin glargine with or without  metformin and/or thiazolidinedione.

### Monotherapy
In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, Exenatide 5 mcg BID (n=77), Exenatide 10 mcg BID (n=78), or placebo BID (n=77) was used as monotherapy in patients with entry HbA1c ranging from 6.5% to 10%. All patients assigned to Exenatide initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive Exenatide 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. Exenatide or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were Caucasian, 26% West Asian, 3% Hispanic, 3% Black, and 0.4% 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, Exenatide 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in HbA1c from baseline at Week 24 (Table 6).

### Combination Therapy with Oral Antihyperglycemic Medicines
Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of Exenatide in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone, a  sulfonylurea alone, or metformin in combination with a sulfonylurea. In addition, a 16-week, placebo-controlled trial was conducted where Exenatide was added to existing  thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control.
In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned to receive Exenatide 5 mcg bid, Exenatide 10 mcg bid, or placebo bid before the morning and evening meals, in addition to their existing oral anti diabetic agent. All patients assigned to Exenatide initially received 5 mcg bid for 4 weeks. After 4 weeks, those patients either continued to receive Exenatide 5 mcg BID or had their dose increased to 10 mcg  bid. Patients assigned to placebo received placebo bid throughout the study. A total of 1446 patients were randomized in the three 30-week trials: 991 (69%) were Caucasian, 224 (16%) Hispanic, and 174 (12%) 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, Exenatide (n=121) or placebo (n=112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without  metformin. Randomization to Exenatide or placebo was stratified based on whether the patients were receiving metformin. Exenatide treatment was initiated at a dose of 5 mcg bid for 4 weeks then increased to 10 mcg bid for 12 more weeks. Patients assigned to placebo received placebo BID throughout the study. Exenatide or placebo was injected subcutaneously before the morning and evening meals. In this trial, 79% of patients were taking a thiazolidinedione and metformin and 21% were taking a thiazolidinedione alone. The majority of patients (84%) were Caucasian, 8% Hispanic, and 3% Black. The mean baseline HbA1c values were 7.9% for Exenatide and placebo.
The primary endpoint in each study was the mean change in HbA1c from baseline to study end (or early discontinuation). Table 7 summarizes the study results for the 30- and 16-week clinical trials.
HbA1c
The addition of Exenatide to a regimen of metformin, a sulfonylurea, or both, resulted in statistically significant reductions from baseline in HbA1c compared with patients receiving placebo added to these agents in the three controlled trials (Table 7).
In the 16-week trial of Exenatide add-on to thiazolidinediones, with or without metformin, Exenatide resulted in statistically significant reductions from baseline in HbA1c compared with patients receiving placebo (Table 7).
Postprandial Glucose
Postprandial glucose was measured after a mixed meal tolerance test in 9.5% of patients participating in the 30-week add-on to metformin, add-on to sulfonylurea, and add-on to metformin  in combination with sulfonylurea clinical trials. In this pooled subset of patients, Exenatide reduced postprandial plasma glucose concentrations in a dose-dependent manner. The mean (SD) change in 2-hour postprandial glucose concentration following administration of Exenatide at Week 30 relative to baseline was 63 (65) mg/dL for 5 mcg BID (n=42), 71 (73) mg/dL for 10 mcg BID (n=52), and +11 (69) mg/dL for placebo BID (n=44).

### Combination with Insulin Glargine
A 30-week, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of Exenatide (n=137) versus placebo (n=122) when added to titrated  insulin glargine, with or without metformin and/or thiazolidinedione, in patients with type 2 diabetes with inadequate glycemic control.
All patients assigned to Exenatide initially received 5 mcg bid for 4 weeks. After 4 weeks, those patients assigned to Exenatide had their dose increased to 10 mcg bid. Patients assigned to placebo received placebo bid throughout the trial. Exenatide or placebo was injected subcutaneously before the morning and evening meals. Patients with an HbA1c 8.0% decreased their prestudy dose of insulin glargine by 20% and patients with an HbA1c 8.1% maintained their current dose of insulin glargine. Five weeks after initiating randomized treatment, insulin doses were titrated with guidance from the investigator toward predefined fasting glucose targets according to the dose titration algorithm provided in Table 9. The majority of patients (78%) were Caucasian, 10% American Indian or Alaska Native, 9% Black, 3% Asian, and 0.8% of multiple origins.
The primary endpoint was the change in HbA1c from baseline to Week 30. Compared to placebo, Exenatide 10 mcg  bid resulted in statistically significant reductions in HbA1c from baseline at Week 30 (Table 8) in patients receiving titrated  insulin glargine.

# How Supplied
Exenatide is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide.
The following packages are available:
5 mcg per dose, 60 doses, 1.2 mL prefilled pen, NDC 66780-210-07
10 mcg per dose, 60 doses, 2.4 mL prefilled pen, NDC 66780-212-01

## Storage
- Prior to first use, Exenatide must be stored refrigerated at 36F to 46F (2C to 8C).
- After first use, Exenatide can be kept at a temperature not to exceed 77F (25C).
- Do not freeze. Do not use Exenatide if it has been frozen.
- Exenatide should be protected from light.
- The pen should be discarded 30 days after first use, even if some drug remains in the pen.
- Use a puncture-resistant container to discard the needles. Do not reuse or share needles.
- Exenatide should not be used past the expiration date.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information

# Precautions with Alcohol
Alcohol-Exenatide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Exenatide
- Bydureon

# Look-Alike Drug Names
There is limited information about the Look-alike drug names.

# Drug Shortage Status

# Price