Drug: Bydureon

BYDUREON (exenatide extended-release for injectable suspension) is supplied as a sterile powder to be suspended in diluent and administered by subcutaneous injection. Exenatide is a 39-amino acid synthetic peptide amide with an empirical formula of C 184H282N50O60S and a 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-Val­Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 BYDUREON is a white to off-white powder that is available in a dosage strength of 2 mg exenatide per vial or per pen. Exenatide is incorporated in an extended-release microsphere formulation containing the 50:50 poly(D,L-lactide-co-glycolide) polymer (37.2 mg per dose) along with sucrose (0.8 mg per dose). The powder must be suspended in the diluent prior to injection. The diluent for the BYDUREON vial is supplied in a prefilled syringe within each single -dose tray. The diluent for the BYDUREON Pen is contained within each single -dose pen. Each configuration contains sufficient diluent to deliver 0.65 mL. The diluent is a clear, colorless to pale-yellow solution composed of carboxymethylcellulose sodium (19 mg), polysorbate 20 (0.63 mg), sodium phosphate monobasic monohydrate (0.61 mg), sodium phosphate dibasic heptahydrate (0.51 mg), sodium chloride (4.1 mg), and water for injection. Sodium h ydroxide may be added during manufacture of BYDUREON Pen for pH adjustment.

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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. The safety of BYDUREON was assessed in five comparator -controlled trials in patients who entered the studies not achieving adequate glycemic control on their current therapy. In a double-blind 26-week trial, patients on diet and exercise were treated with BYDUREON 2 mg once every 7 days (weekly), sitagliptin 100 mg daily, pioglitazone 45 mg daily, or metformin 2000 mg daily. In a double-blind 26-week trial, patients on metformin were treated with BYDUREON 2 mg once every 7 days (weekly), sitagliptin 100 mg daily, or pioglitazone 45 mg daily. In an open-label 26-week trial, patients on metformin or metformin plus sulfonylurea were treated with BYDUREON 2 mg once every 7 days (weekly) or optimized insulin glargine. In two open ­label 24-to 30-week studies, patients on diet and exercise or metformin, a sulfonylurea, a thiazolidinedione, or combination of oral agents were treated with BYDUREON 2 mg once every 7 days (weekly) or BYETTA 10 mcg twice daily. Withdrawals The incidence of withdrawal due to adverse events was 4.9% (N=45) for BYDUREON -treated patients, 4.9% (N=13) for BYETTA-treated patients, and 2.0% (N=23) for other comparator ­treated patients in the five comparator-controlled 24-to 30-week trials. The most common adverse reactions leading to withdrawal for BYDUREON -treated patients were nausea 0.5% (N=5) versus 1.5% (N=4) for BYETTA and 0.3% (N=3) for other comparators, injection -site nodule 0.5% (N=5) versus 0.0% for BYETTA and 0.0% for other comparators, diarrhea 0.3% (N=3) versus 0.4% (N=1) for BYETTA and 0.3% (N=3) for other comparators, injection -site reaction 0.2% (N=2) versus 0.0% for BYETTA and 0.0% for other comparators, and headache 0.2% (N=2) versus 0.0% for BYETTA and 0.0% for other comparators. Hypoglycemia Table 1 summarizes the incidence and rate of minor hypoglycemia in the five comparator ­controlled 24-to 30-week trials of BYDUREON used as monotherapy or as add-on to metformin, a sulfonylurea, a thiazolidinedione, or combination of these oral antidiabetic agents. In these trials, an event was classified as minor hypoglycemia if there were symptoms of hypoglycemia with a concomitant glucose < 54 mg/dL and the patient was able to self-treat. Table 1: Incidence (% of Subjects) and Rate (Episodes/Subject Year) of Minor† Hypoglycemia in the Monotherapy Trial and in the Combination Therapy Trials
26-Week Monotherapy Trial BYDUREON 2 mg (N = 248) 2.0% (0.05) Sitagliptin 100 mg (N = 163) 0.0% (0.00) Pioglitazone 45 mg (N = 163) 0.0% (0.00) Metformin 2000 mg QD (N = 246) 0.0% (0.00) 26-Week Add-On to Metformin Trial BYDUREON 2 mg (N = 160) 1.3% (0.03) Sitagliptin 100 mg (N = 166) 3.0% (0.12) Pioglitazone 45 mg (N = 165) 1.2% (0.03) 26-Week Add-On to Metformin or Metformin + Sulfonylurea Trial With Concomitant Sulfonylurea Use (N = 136) BYDUREON 2 mg (N = 70) 20.0% (1.11) Titrated Insulin Glargine (N = 66) 43.9% (2.87) Without Concomitant Sulfonylurea Use (N = 320) BYDUREON 2 mg (N = 163) 3.7% (0.11) Titrated Insulin Glargine‡ (N = 157) 19.1% (0.64) 24-Week Monotherapy or Add-On to Metformin, a Sulfonylurea, a Thiazolidinedione, or Combination of Oral Agents Trial With Concomitant Sulfonylurea Use (N = 74) BYDUREON 2 mg (N = 40) 12.5% (0.72) BYETTA 10 mcg (N = 34) 11.8% (0.31) Without Concomitant Sulfonylurea Use (N = 178) BYDUREON 2 mg (N = 89) 0.0% (0.00) BYETTA 10 mcg (N = 89) 0.0% (0.00) 30-Week Monotherapy or Add-On to Metformin, a Sulfonylurea, a Thiazolidinedione, or Combination of Oral Agents Trial With Concomitant Sulfonylurea Use (N = 107) BYDUREON 2 mg (N = 55) 14.5% (0.55) BYETTA 10 mcg (N = 52) 15.4% (0.37) Without Concomitant Sulfonylurea Use (N = 186) BYDUREON 2 mg (N = 93) 0.0% (0.00) BYETTA 10 mcg (N = 93) 1.1% (0.02) N = number of intent-to-treat patients. Note: Percentages are based on the number of intent-to-treat patients in each treatment group.
† Reported event that has symptoms consistent with hypoglycemia with a concomitant glucose < 54 mg/dL and the patient was able to self-treat.
‡ Insulin glargine was dosed to a target fasting glucose concentration of 72 to 100 mg/dL. The mean dose of insulin glargine was 10 Units/day at baseline and 31 Units/day at endpoint. There were no reported events of major hypoglycemia in these five comparator-controlled 24-to 30-week trials. Major hypoglycemia was defined as loss of consciousness, seizure, or coma (or other mental status change consistent with neuroglycopenia in the judgment of the investigator or physician) which resolved after administration of glucagon or glucose or required third -party assistance to resolve because of severe impairment in consciousness or behavior. Patients were to have a concomitant glucose < 54 mg/dL. Immunogenicity Anti-exenatide antibodies were measured at prespecified intervals (4-14 weeks) in all BYDUREON-treated patients (N=918) in the five comparator -controlled studies of BYDUREON. In these five trials, 452 BYDUREON -treated patients (49%) had low titer antibodies ( ≤ 125) to exenatide at any time during the trials and 405 BYDUREON -treated patients (45%) had low titer antibodies to exenatide at study endpoint (24 -30 weeks). The level of glycemic control in these patients was generally comparable to that observed in the 379 BYDUREON-treated patients (43%) without antibody titers. An additional 107 BYDUREON ­treated patients (12%) had higher titer antibodies at endpoint. Of these patients, 50 (6% overall) had an attenuated glycemic response to BYDUREON ( < 0.7% reduction in HbA1c); the remaining 57 (6% overall) had a glycemic response comparable to that of patients without antibodies [see WARNINGS AND PRECAUTIONS]. In the 30-week trial in which anti-exenatide antibody assessments were performed at baseline and at 4 -week intervals from week 6 to week 30, the mean anti-exenatide antibody titer in the BYDUREON -treated patients peaked at week 6 then declined by 56% from this peak by week 30. A total of 246 patients with antibodies to exenatide in the BYETTA and BYDUREON 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 BYDUREON Tables 2 and 3 summarize adverse reactions with an incidence ≥ 5% reported in the five comparator-controlled 24-to 30-week trials of BYDUREON used as monotherapy or as add -on to metformin, a sulfonylurea, a thiazolidinedione, or combination of these oral antidiabetic agents. Table 2: Treatment-Emergent Adverse Reactions Reported in ≥ 5% of BYDUREON-Treated Patients in Monotherapy Trial
26-Week Monotherapy Trial   BYDUREON 2 mg
N = 248 % Sitagliptin 100 mg
N = 163 % Pioglitazone 45 mg
N = 163 % Metformin 2000 mg
N = 246 % Nausea 11.3 3.7 4.3 6.9 Diarrhea 10.9 5.5 3.7 12.6 Injection-site nodule† 10.5 6.7 3.7 10.2 Constipation 8.5 2.5 1.8 3.3 Headache 8.1 9.2 8.0 12.2 Dyspepsia 7.3 1.8 4.9 3.3 N = number of intent-to-treat patients.
Note: Percentages are based on the number of intent-to-treat patients in each treatment group.
† Patients in the sitagliptin, pioglitazone, and metformin treatment groups received weekly placebo injections. Table 3: Treatment-Emergent Adverse Reactions Reported in ≥ 5% of BYDUREON-Treated Patients in 24to 30-Week Add-On Combination Therapy Trials
26-Week Add-On to Metformin Trial   BYDUREON 2 mg
N = 160 % Sitagliptin 100 mg
N = 166 % Pioglitazone 45 mg
N = 165 % Nausea 24.4 9.6 4.8 Diarrhea 20.0 9.6 7.3 Vomiting 11.3 2.4 3.0 Headache 9.4 9.0 5.5 Constipation 6.3 3.6 1.2 Fatigue 5.6 0.6 3.0 Dyspepsia 5.0 3.6 2.4 Decreased appetite 5.0 1.2 0.0 Injection-site pruritus† 5.0 4.8 1.2 26-Week Add-On to Metformin or Metformin + Sulfonylurea Trial   BYDUREON 2 mg
N = 233 % Insulin Glargine Titrated
N = 223 %   Nausea 12.9 1.3   Headache 9.9 7.6   Diarrhea 9.4 4.0   Injection-site nodule 6.0 0.0   30-Week Monotherapy or as Add-On to Metformin, a Sulfonylurea, a Thiazolidinedione, or Combination of Oral Agents Trial   BYDUREON 2 mg
N = 148 % BYETTA 10 mcg
N = 145 %   Nausea 27.0 33.8   Diarrhea 16.2 12.4   Vomiting 10.8 18.6   Injection-site pruritus 18.2 1.4   Constipation 10.1 6.2   Gastroenteritis viral 8.8 5.5   Gastroesophageal reflux disease 7.4 4.1   Dyspepsia 7.4 2.1   Injection-site erythema 7.4 0.0   Fatigue 6.1 3.4   Headache 6.1 4.8   Injection-site hematoma 5.4 11.0   24-Week Monotherapy or as Add-On to Metformin, a Sulfonylurea, a Thiazolidinedione, or Combination of Oral Agents Trial   BYDUREON 2 mg
N = 129 % BYETTA 10 mcg
N = 123 %   Nausea 14.0 35.0   Diarrhea 9.3 4.1   Injection-site erythema 5.4 2.4   N = number of intent-to-treat patients.
Note: Percentages are based on the number of intent-to-treat patients in each treatment group.
† Patients in the sitagliptin, pioglitazone, and metformin treatment groups received weekly placebo injections. Nausea was the most common adverse reaction associated with initiation of treatment with BYDUREON, and usually decreased over time. Injection-Site Reactions In the five comparator-controlled 24-to 30-week trials, injection-site reactions were observed more frequently in patients treated with BYDUREON (17.1%) than in patients treated with BYETTA (12.7%), titrated insulin glargine (1.8%), or those patients who received placebo injections (sitagliptin (10.6%), pioglitazone (6.4%), and metformin (13.0%) treatment groups). These reactions for patients treated with BYDUREON were more commonly observed in antibody-positive patients (14.2%) compared with antibody-negative patients (3.1%), with a greater incidence in those with higher titer antibodies [see WARNINGS AND PRECAUTIONS]. Incidence of injection-site reactions for patients treated with BYETTA was similar for antibody-positive patients (5.8%) and antibody-negative patients (7.0%). One percent of patients treated with BYDUREON withdrew due to injection-site adverse reactions (injection-site mass, injection-site nodule, injection-site pruritus, and injection-site reaction). Subcutaneous injection-site nodules may occur with the use of BYDUREON. In a separate 15-week study in which information on nodules were collected and analyzed, 24 out of 31 subjects (77%) experienced at least 1 injection -site nodule during treatment; 2 subjects (6.5%) reported accompanying localized symptoms. The mean duration of events was 27 days. The formation of nodules is consistent with the known properties of the microspheres used in BYDUREON. BYETTA In three 30-week controlled trials of BYETTA (N=963) add -on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence of ≥ 1% and reported more frequently than with placebo included nausea (44% BYETTA, 18% placebo), vomiting (13% BYETTA, 4% placebo), diarrhea (13% BYETTA, 6% placebo), feeling jittery (9% BYETTA, 4% placebo), dizziness (9% BYETTA, 6% placebo), headache ( 9% BYETTA, 6% placebo), dyspepsia (6% BYETTA, 3% placebo), asthenia (4% BYETTA, 2% placebo), gastroesophageal reflux (3% BYETTA, 1% placebo), hyperhidrosis (3% BYETTA, 1% placebo), and decreased appetite (1% BYETTA, < 1% placebo). Similar types of adverse r eactions were observed in 24-week and 16-week controlled trials of BYETTA used as monotherapy or as add ­on to a thiazolidinedione, with or without metformin, respectively. Postmarketing Experience BYDUREON Allergy/Hypersensitivity: injection-site reactions [see WARNINGS AND PRECAUTIONS]. BYETTA 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]. Drug Interactions: increased international normalized ratio (INR), sometimes associated with bleeding, with concomitant warfarin use [see DRUG INTERACTIONS]. Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehyd ration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death [see INDICATIONS AND USAGE 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 tran splant dysfunction [see WARNINGS AND PRECAUTIONS]. Skin and Subcutaneous Tissue Disorders: alopecia Read the Bydureon (exenatide) Side Effects Center for a complete guide to possible side effectsLearn More »

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Recommended Dosing BYDUREON (2 mg per dose) should be administered once every 7 days (weekly). The dose can be administered at any time of day, with or without meals. Missed Dose If a dose is missed, it should be administered as soon as noticed, provided the next regularly scheduled dose is due at least 3 days later. Thereafter, patients can resume their usual dosing schedule of once every 7 days (weekly). If a dose is missed and the next regularly scheduled dose is due 1 or 2 days later, the patient should not administer the missed dose and instead resume BYDUREON with the next regularly scheduled dose. Changing Weekly Dosing Schedule The day of weekly administration can be changed if necessary as long as the last dose was administered 3 or more days before. Administration BYDUREON must be injected immediately after the dose is prepared. BYDUREON is administered as a subcutaneous (SC) injection in the abdomen, thigh, or upper arm region. Advise patients to use a different injection site each week when injecting in the same region. BYDUREON must not be administered intravenously or intramuscularly. BYDUREON is intended for patient self-administration. Prior to initiation of BYDUREON, patients should be trained by their healthcare professional. For the BYDUREON Pen, study data demonstrated that training reduced the risk of administration errors such as inadequate mixing or incomplete dosing. Patients using the BYDUREON Pen should be trained on proper mixing and injection technique to ensure the product is adequately mixed and a full dose is delivered. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations. The instructions can also be found at www.bydureon.com. Changing From BYETTA To BYDUREON Prior treatment with BYETTA is not required when initiating BYDUREON therapy. If the decision is made to start BYDUREON in an appropriate patient already taking BYETTA, BYETTA should be discontinued. Patients changing from BYETTA to BYDUREON may experience transient (approximately 2 weeks) elevations in blood glucose concentrations.

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Orally Administered Drugs Exenatide slows gastric emptying. Therefore, BYDUREON has the potential to reduce the rate of absorption of orally administered drugs. Use caution when administering oral medications with BYDUREON [see CLINICAL PHARMACOLOGY]. In patients with type 2 diabetes, BYDUREON did not affect the absorption of orally administered acetaminophen to any clinically relevant degree. Warfarin BYDUREON has not been studied with warfarin. However, in a drug interaction study, BYETTA did not have a significant effect on INR [see CLINICAL PHARMACOLOGY]. There have been postmarketing reports for BYETTA of increased I NR with concomitant use of warfarin, sometimes associated with bleeding [see ADVERSE REACTIONS]. In patients taking warfarin, the INR should be monitored more frequently after initiating BYDUREON . Once a stable INR has been documented, the INR can be monitored at the intervals usually recommended for patients on warfarin. Read the Bydureon Drug Interactions Center for a complete guide to possible interactions Learn More »

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BYDUREON is an extended-release formulation of exenatide, administered as an injection once every 7 days (weekly). Type 2 Diabetes Mellitus BYDUREON is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies]. Important Limitations Of Use Because of the uncertain relevance of the rat thyroid C-cell tumor findings to humans, prescribe BYDUREON only to patients for whom the potential benefits are considered to outweigh the potential risk. BYDUREON is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. BYDUREON is not a substitute for insulin. BYDUREON 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 BYDUREON with insulin has not been studied and cannot be recommended. BYDUREON and BYETTA® (exenatide) injection both contain the same active ingredient, exenatide, and therefore should not be used together. Based on postmarketing data, exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. BYDUREON 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 p ancreatitis while using BYDUREON. Other antidiabetic therapies should be considered in patients with a history of pancreatitis.

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Medullary Thyroid Carcinoma BYDUREON is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Hypersensitivity BYDUREON is contraindicated in patients with a prior serious hypersensitivity reaction to exenatide or to any of the product components. Last reviewed on RxList: 3/19/2015
This monograph has been modified to include the generic and brand name in many instances.

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There were no reports of overdose in the five comparator -controlled 24-to 30-week trials of BYDUREON. Effects of overdoses with BYETTA in clinical studies included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations, including severe hypoglycemia requiring parenteral glucose administration. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

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Dosage Forms And Strengths BYDUREON exenatide extended-release for injectable suspension is available as:
  • BYDUREON single-dose tray which contains one vial of 2 mg exenatide, one vial connector, one prefilled diluent syringe, and two needles (one provided as a spare).
  • BYDUREON Pen. Each single-dose pen contains 2 mg of exenatide and diluent, and includes one needle. Each carton contains one spare needle.
Do not substitute needles or any other components provided with BYDUREON. See Storage and Handling for additional information. BYDUREON (exenatide extended-release for injectable suspension) for once every 7 days (weekly) subcutaneous administration is supplied as: BYDUREON single-dose tray, supplied in cartons that contain four single-dose trays (NDC 66780-219-04). Each single-dose tray contains:
  • One vial containing 2 mg exenatide (as a white to off-white powder)
  • One prefilled syringe delivering 0.65 mL diluent
  • One vial connector
  • Two custom needles (23G, 5/16”) specific to this delivery system (one is a spare needle)
BYDUREON Pen, supplied in cartons that contain four single -dose pens and one spare needle (NDC 0310-6530-04). Each single-dose pen contains:
  • One pen containing 2 mg of exenatide (as a white to off -white powder) and delivering 0.65 mL diluent.
  • One custom needle (23G, 9/32”) specific to this delivery system.
Do not substitute needles or any other components provided with BYDUREON. Storage And Handling
  • BYDUREON should be stored in the refrigerator at 36 °F to 46°F (2°C to 8°C), up to the expiration date or until preparing for use. BYDUREON should not be used past the expiration date. The expiration date can be found on the carton, on the cover of the single ­dose tray, or on the pen label.
  • Do not freeze BYDUREON. Do not use BYDUREON if it has been frozen. Protect from light.
  • BYDUREON can be kept at room temperature not to exceed 77°F (25 °C) [see USP Controlled Room Temperature] for no more than a total of 4 weeks, if needed.
  • Use the diluent only if it is clear and free of particulate matter.
  • After suspension, the mixture should be white to off-white and cloudy.
  • BYDUREON must be administered immediately after the exenatide powder is suspended in the diluent.
  • Use a puncture-resistant container to discard BYDUREON with the needle still attached. Do not reuse or share needles or syringes.
  • Keep out of the reach of children.
Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850. By: Amylin Ohio LLC West Chester, OH 45071. Approved: March 2015 Last reviewed on RxList: 3/19/2015
This monograph has been modified to include the generic and brand name in many instances.

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Risk Of Thyroid C-cell Tumors In both genders of rats, exenatide extended-release caused a dose-related and treatment-duration– dependent increase in the incidence of thyroid C -cell tumors (adenomas and/or carcinomas) at clinically relevant exposures compared to controls [see Nonclinical Toxicology]. A statistically significant increase in malign ant thyroid C-cell carcinomas was observed in female rats receiving exenatide extended-release at 25-times clinical exposure compared to controls and higher incidences were noted in males above controls in all treated groups at ≥ 2-times clinical exposure. The potential of exenatide extended-release to induce C-cell tumors in mice has not been evaluated. Other GLP-1 receptor agonists have also induced thyroid C -cell adenomas and carcinomas in male and female mice and rats at clinically relevant exposures. It is unknown whether BYDUREON will cause thyroid C -cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of exenatide extended-release–induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinic al studies. Serum calcitonin was not assessed in the clinical trials supporting the approval of BYDUREON [see BOXED WARNING and CONTRAINDICATIONS]. Serum calcitonin is a biological marker of MTC. Patients with MTC usually have calcitonin values > 50ng/L. Patients with thyroid nodules noted on physical examination or neck imaging should be referred to an endocrinologist for further evaluation. Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with BYDUREON. Such monitoring may increase the risk of unnecessary procedures, due to the low specificity of serum calcitonin testing for MTC and a high background incidence of thyroid disease. If serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation [see PATIENT INFORMATION]. Acute Pancreatitis Based on postmarketing data, exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYDUREON, 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, BYDUREON should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, BYDUREON should not be restarted. Consider antidiabetic therapies other than BYDUREON in patients with a history of pancreatitis. Hypoglycemia The risk of hypoglycemia is increased when exenatide is used in combination with a sulfonylurea. Therefore, patients receiving BYDUREON and a sulfonylurea may require a lower dose of the sulfonylurea to minimize the risk of hypoglycemia. It is also possible that the use of BYDUREON with other glucose-independent insulin secretagogues (e.g., meglitinides) could increase the risk of hypoglycemia. For additional information on glucose-dependent effects see CLINICAL PHARMACOLOGY. Renal Impairment BYDUREON should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease and should be used with caution in patients with renal transplantation [see Use in Specific Populations]. In patients with end-stage renal disease receiving dialysis, single doses of BYETTA 5 mcg were not well tolerated due to gastrointestinal side effects. Because BYDUREON may induce nausea and vomiting with transi ent hypovolemia, treatment may worsen renal function. Use BYDUREON with caution in patients with moderate renal impairment (creatinine clearance 30 -50 mL/min) [see Use In Specific Populations and CLINICAL PHARMACOLOGY]. BYDUREON has not been studied in patients with end-stage renal disease or severe renal impairment. There have been postmarketing reports of altered renal function with exenatide, 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 suppor tive 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 BYDUREON is not recommended in patients with severe gastrointestinal disease. Immunogenicity Patients may develop antibodies to exenatide following treatment with BYDUREON. Anti ­exenatide antibodies were measured in all BYDUREON -treated patients in the five comparator ­controlled 24-to 30-week studies of BYDUREON. In 6% of BYDUREON-treated patients, antibody formation was associated with an attenuated glycemic response. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered [see ADVERSE REACTIONS]. Hypersensitivity There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) in patients treated with exenatide. If a hypersensitivity reaction occurs, the patient should discontinue BYDUREON and other suspect medications and promptly seek medical advice [see ADVERSE REACTIONS]. Injection-Site Reactions There have been postmarketing reports of serious injection-site reactions (e.g., abscess, cellulitis, and necrosis), with or without subcutaneous nodules, with the use of BYDUREON. Isolated cases required surgical intervention [see ADVERSE REACTIONS]. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYDUREON or any other antidiabetic drug. Patient Counseling Information See FDA-approved Medication Guide. Prior to initiation of BYDUREON, patients should be trained by their healthcare professional. Inform patients about the potential risks and benefits of BYDUREON and of alternative modes of therapy. Also inform patients about the importance of diabetes self -management practices, such as regular physical activity, adhering to meal planning, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Risk Of Thyroid C-cell Tumors Inform patients that exenatide extended-release causes benign and malignant thyroid C -cell tumors in rats and that the human relevance of this finding is unknown. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia, or dyspnea) [see WARNINGS AND PRECAUTIONS]. Risk Of Pancreatitis Inform patients treated with BYDUREON of the potential risk for pancreatitis. Explain that persistent severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue BYDUREON promptly and contact their healthcare provider if persistent severe abdominal pain occurs [see WARNINGS AND PRECAUTIONS]. Risk Of Hypoglycemia The risk of hypoglycemia is increased when BYDUREON is used in combination with an agent that induces hypoglycemia, such as a sulfonylurea [ see WARNINGS AND PRECAUTIONS]. Explain the symptoms, treatment, and conditions that predispose to the development of hypoglycemia. While the patient's usual instructions for hypoglycemia management do not need to be changed, these instructions should be reviewed and reinforced when initiating BYDUREON therapy, particularly when concomitantly administered with a sulfonylurea [see WARNINGS AND PRECAUTIONS]. Risk Of Renal Impairment Inform patients treated with BYDUREON of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs [see WARNINGS AND PRECAUTIONS]. Risk Of Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of exenatide. If symptoms of hypersensitivity reactions occur, patients must stop taking BYDUREON and seek medical advice promptly [see WARNINGS AND PRECAUTIONS]. Risk Of Injection-Site Reactions Inform patients that there have been postmarketing reports of serious injection-site reactions with or without subcutaneous nodules, with the use of BYDUREON. Isolated cases of injection -site reactions required surgical intervention. Advise patients to seek medical advice if symptomatic nodules occur, or for any signs or symptoms of abscess, cellulitis, or necrosis [see WARNINGS AND PRECAUTIONS]. Use In Pregnancy Advise patients to inform their healthcare provider if they are pregnant or intend to become pregnant [see Use in Specific Populations]. Instructions Patients should be trained on how to use BYDUREON properly prior to self -administration. Instruct patients on proper mixing and injection technique to ensure the product is adequately mixed and a full dose is delivered. Refer patients to the accompanying Instructions for Use for complete administration instructions with illustrations. Each dose of BYDUREON should be administered as a subcutaneous injection at any time on the dosing day, with or without meals. Patients should be informed that the day of once every 7 days (weekly) administration can be changed if necessary as long as the last dose was administered 3 or more days before. If a dose is missed, it should be administered as soon as noticed, provided the next regularly scheduled dose is due at least 3 days later. Thereafter, patients can resume their usual once every 7 days (weekly) dosing schedule. If a dose is missed and the next regularly scheduled dose is due in 1 or 2 days, the patient should not administer the missed dose and instead resume BYDUREON with the next regularly scheduled dose [see DOSAGE AND ADMINISTRATION]. Counsel patients that they should never share BYDUREON with another person, even if the needle is changed. Sharing of BYDUREON or needles between patients may pose a risk of transmission of infection. If a patient is currently taking BYETTA, it should be discontinued upon starting BYDUREON. Patients formerly on BYETTA who start BYDUREON may experience transient elevations in blood glucose concentrations, which generally improve within the first 2 weeks after initiation of therapy [see DOSAGE AND ADMINISTRATION and Clinical Studies]. Treatment with BYDUREON may also result in nausea, particularl y upon initiation of therapy [see ADVERSE REACTIONS Inform patients about the importance of proper storage of BYDUREON, injection technique, and dosing [see DOSAGE AND ADMINISTRATION and HOW SUPPLIED/Storage and Handling]. The patient should read the BYDUREON Medication Guide and the Instructions for Use before starting BYDUREON therapy and review them each time the prescription is refilled. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility A 104-week carcinogenicity study was conducted with exenatide extended -release in male and female rats at doses of 0.3, 1.0, and 3.0 mg/kg (2 -, 9-, and 26-times human systemic exposure based on AUC, respectively) administered by subcutaneous injection every other week. A statistically significant increase in thyroid C -cell tumor incidence was observed in both males and females. The incidence of C-cell adenomas was statistically significantly increased at all doses (27%-31%) in females and at 1.0 and 3.0 mg/kg (46% and 47%, respectively) in males compared with the control group (13% for males and 7% for females). A statistically significantly higher incidence of C-cell carcinomas occurred in the high-dose group females (6%), while numerically higher incidences of 3%, 7%, and 4% (nonstatistically significant versus controls) were noted in the low-, mid-, and high-dose group males compared with the control group (0% for both males and females) . An increase in benign fibromas was seen in the skin subcutis at injection sites of males given 3 mg/kg. No treatment -related injection-site fibrosarcomas were observed at any dose. The human relevance of these findings is currently unknown. A 104-week carcinogenicity study was conducted with exenatide, the active ingredient in BYDUREON, in male and female rats at doses of 18, 70, or 250 mcg/kg/day (3-, 6-, and 27­times human systemic exposure based on AUC, respectively) administered by once -daily bolus subcutaneous 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. In a 104-week carcinogenicity study with exenatide, the active ingredient in BYDUREON, in male and female mice at doses of 18, 70, or 250 mcg/kg/day administered by once-daily bolus subcutaneous injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 16 times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC. The carcinogenicity of exenatide extended-release has not been evaluated in mice. BYDUREON and exenatide, the active ingredient in BYDUREON, were 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 exenatide, the active ingredient in BYDUREON, at twice -daily subcutaneous 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 148 times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC. Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of BYDUREON use in pregnant women. In rats, exenatide extended-release administered during the major period of organogenesis reduced fetal growth and produced skeletal ossification deficits in association with maternal effects; exenatide extended-release was not teratogenic in rats. In animal developmental studies, exenatide, the active ingredient of BYDUREON, caused cleft palate, irregular skeletal ossification, and an increased number of neonatal deaths. BYDUREON should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Fetuses from pregnant rats given subcutaneous doses of exenatide extended -release at 0.3, 1, or 3 mg/kg on gestation days 6, 9, 12, and 15 demonstrated reduced fetal growth at all doses and produced skeletal ossification deficits at 1 and 3 mg/kg in association wi th maternal effects (decreased food intake and decreased body weight gain). There was no evidence of malformations. Doses of 0.3, 1, and 3 mg/kg correspond to systemic exposures of 3, 7, and 17 times, respectively, the human exposure resulting from the rec ommended dose of 2 mg/week, based on area under the time-concentration curve (AUC) [see Nonclinical Toxicology]. Female mice given subcutaneous doses of exenatide, the active ingredient of BYDUREON, at 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 148 times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC [see Nonclinical Toxicology]. In developmental toxicity studies, pregnant animals received exenatide, the active ingredient of BYDUREON, subcutaneously during organogenesis. Specifically, fetuses from pregnant rabbits given subcutaneous doses of exenatide at 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 4 times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC. Fetuses from pregnant mice given subcutaneous doses of exenatide at 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 that is equivalent to the human exposure resulting from the recommended dose of 2 mg/week, based on AUC [see Nonclinical Toxicology]. Lactating mice given subcutaneous doses of exenatide, the active ingredient of BYDUREON, at 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 that is equivalent to the human exposure resulting from the recommended dose of 2 mg/week, based on AUC [see Nonclinical Toxicology]. 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. Nursing Mothers Exenatide is present in the milk of lactating mice at concentrations less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing. It is not known whether exenatide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for exenatide extended -release in animal studies, a decision should be made whether to discontinue nursing or to discontinue BYDUREON, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of BYDUREON have not been established in pediatric patients. BYDUREON is not recommended for use in pediatric patients. Geriatric Use In the five comparator-controlled 24-to 30-week trials, BYDUREON was studied in 132 patients (16.6%) who were at least 65 years old and 20 patients who were at least 75 years old. No differences in safety (N=152) and efficacy (N=52) were observed between these patients and younger patients, but the small sample size for patients ≥ 75 years old limits conclusions. In separate trials, BYETTA was studied in 282 patients at least 65 years old and in 16 patients at least 75 years old. No differences in safety and efficacy were observed between these patients and younger patients, but the small sample size for patients ≥ 75 years old limits conclusions. Because elderly patients are more likely to have decreased renal function, use caution when initiating BYDUREON in the elderly. Renal Impairment BYDUREON 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. Use BYDUREON with caution in patients with moderate renal impairment (creatinine clearance 30-50 mL/min) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. 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 impairment is not expected to affect blood concentrations of exenatide [see CLINICAL PHARMACOLOGY]. Last reviewed on RxList: 3/19/2015
This monograph has been modified to include the generic and brand name in many instances.

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