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Bydureon——每周注射一次的长效缓释注射悬液在欧洲及美国获批准上市
HIGHLIGHTS OF PRESCRIBING INFORMATION
BYDUREON is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1.1, 14). BYDUREON is an extended-release formulation of exenatide. Do not coadminister with BYETTA. Important Limitations of Use • Not recommended as first-line therapy for patients inadequately controlled on diet and exercise ( 1.2). • Should not be used to treat type 1 diabetes or diabetic ketoacidosis ( 1.2). • Use with insulin has not been studied and is not recommended ( 1.2). • Has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis ( 1.2, 5.2). DOSAGE AND ADMINISTRATION • Administer 2 mg by subcutaneous injection once every seven days (weekly), at any time of day and with or without meals ( 2.1). • Administer immediately after the dose is prepared ( 2.1). DOSAGE FORMS AND STRENGTHS BYDUREON 2 mg exenatide for extended-release injectable suspension has two dosage forms (3): • BYDUREON single-dose tray containing 2 mg vial • BYDUREON Pen single-dose 2 mg pen CONTRAINDICATIONS • Bydureon is contraindicated in patients with personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 ( 4.1). • Bydureon is contraindicated in patients with a prior serious hypersensitivity reaction to exenatide or any of the product components ( 4.2). WARNINGS AND PRECAUTIONS • Thyroid C-cell Tumors: See Boxed Warning ( 5.1). • Pancreatitis: Postmarketing reports with exenatide, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed. Consider other antidiabetic therapies if patient has history of pancreatitis ( 5.2). • Hypoglycemia: When BYDUREON is used in combination with an insulin secretagogue (e.g., a sulfonylurea) or insulin, consider lowering the dose of the secretagogue or insulin to reduce the risk of hypoglycemia ( 5.3). • Renal Impairment: Postmarketing reports with exenatide, sometimes requiring hemodialysis and kidney transplantation. Not recommended if patient has severe renal impairment or end-stage renal disease. Use with caution in patients with renal transplantation or moderate renal impairment ( 5.4, 8.6, 12.3). • Severe Gastrointestinal Disease: Not recommended in patients with severe gastrointestinal disease (e.g., gastroparesis) ( 5.5). • Hypersensitivity: Postmarketing reports with exenatide of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema). In such cases, patients are to discontinue BYDUREON and other suspect medications and promptly seek medical advice ( 5.7). • Injection-site Reactions: There have been postmarketing reports of serious injection-site reactions with or without subcutaneous nodules ( 5.8). • Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYDUREON or any other antidiabetic drug ( 5.9). ADVERSE REACTIONS Most common (≥5%) and occurring more frequently than comparator in clinical trials: nausea, diarrhea, headache, vomiting, constipation, injection-site pruritus, injection-site nodule, and dyspepsia (5.3, 6.1). To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 and www.bydureon.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • May impact absorption of orally administered medications ( 7.1, 12.3). • Warfarin: Postmarketing reports with exenatide of increased INR sometimes associated with bleeding. Monitor INR frequently until stable upon initiation of BYDUREON therapy ( 6.2, 7.2). USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data, may cause fetal harm. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. To report drug exposure during pregnancy call 1-800-633-9081 ( 8.1). • Nursing Mothers: Use caution when administering to a nursing woman ( 8.3). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 9/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE BYDUREON is an extended-release formulation of exenatide, administered as an injection once every 7 days (weekly). 1.1 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 (14)]. 1.2 Important Limitations of Use BYDUREON is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise 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 [see Warnings and Precautions (5.1)]. 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 pancreatitis while using BYDUREON. Other antidiabetic therapies should be considered in patients with a history of pancreatitis [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 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. 2.2 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. 2.3 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. 3 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 How Supplied/Storage and Handling (16.1) for additional information. 4 CONTRAINDICATIONS 4.1 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). 4.2 Hypersensitivity BYDUREON is contraindicated in patients with a prior serious hypersensitivity reaction to exenatide or to any of the product components. 5 WARNINGS AND PRECAUTIONS 5.1 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 (13.1)]. A statistically significant increase in malignant 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 has not been determined. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. BYDUREON is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk of MTC with the use of BYDUREON and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). 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. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 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. 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin The risk of hypoglycemia is increased when exenatide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Patients may require a lower dose of the secretagogue or insulin to reduce the risk of hypoglycemia in this setting [see Adverse Reactions (6.1)]. 5.4 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 (8.6)]. In patients with end-stage renal disease receiving dialysis, single doses of BYETTA 5 mcg were not well tolerated due to gastrointestinal side effects. Because BYDUREON may induce nausea and vomiting with transient 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 (8.6) and Clinical Pharmacology (12.3)]. 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 supportive treatment and discontinuation of potentially causative agents, including exenatide. Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies. 5.5 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. 5.6 Immunogenicity Patients may develop antibodies to exenatide following treatment with BYDUREON. Anti-exenatide antibodies were measured in BYDUREON-treated patients in five of the six 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 (6.1 and 6.2)]. 5.7 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 (6.4)]. 5.8 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 (6.3)]. 5.9 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYDUREON or any other antidiabetic drug. 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)] • Acute Pancreatitis [see Warnings and Precautions (5.2)] • Hypoglycemia [see Warnings and Precautions (5.3)] • Renal Impairment [see Warnings and Precautions (5.4)] • Gastrointestinal Disease [see Warnings and Precautions (5.5)] • Immunogenicity [see Warnings and Precautions (5.6)] • Hypersensitivity [see Warnings and Precautions (5.7)] • Injection-Site Reactions [see Warnings and Precautions (5.8)] 6.1 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 six 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. In an open-label 26-week trial, patients on metformin, a sulfonylurea, metformin plus a sulfonylurea, or metformin plus pioglitazone were treated with BYDUREON 2 mg every 7 days (weekly) or liraglutide 1.8 mg once daily. Withdrawals The incidence of withdrawal due to adverse events was 4.1% (N=57) for BYDUREON-treated patients, 4.9% (N=13) for BYETTA-treated patients, and 2.9% (N=46) for other comparator-treated patients in the six comparator-controlled 24- to 30-week trials. The most common classes of adverse reactions (0.5%) leading to withdrawal for BYDUREON-treated patients were, Gastrointestinal Disorders 1.6% (N=22) versus 4.1% (N=11) for BYETTA and 1.9% (N=30) for other comparators, and Administration Site Conditions 0.8% (N=11) versus 0.0% for BYETTA and 0.2% (N=3) for other comparators. The most frequent events within each of these respective classes were, nausea 0.4% (N=6) for BYDUREON versus 1.5% (N=4) for BYETTA and 0.8% (N=12) for other comparators, and injection-site nodule, 0.4% (N=6) for BYDUREON versus 0.0% for BYETTA and 0.0% for other comparators. Hypoglycemia Table 1 summarizes the incidence and rate of minor hypoglycemia in the six 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.
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 six 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. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to BYDUREON in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. 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 (5.6)]. 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. 6.3 Other Adverse Reactions BYDUREON Tables 2 and 3 summarize adverse reactions with an incidence ≥5% reported in the six 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 (the findings in the BYDUREON are from a sixth comparator-controlled open label trial of BYDUREON are included in Table 3).
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.
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 (5.6)]. 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. Changes in heart rate Increases in heart rate from baseline ranging from 1.5 to 4.5 beats per minute have been observed in comparator-controlled clinical trials. The long-term effects of the increase in heart rate have not been established. 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 reactions 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. 6.4 Postmarketing Experience BYDUREON Allergy/Hypersensitivity: injection-site reactions [see Warnings and Precautions (5.8)]. 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 (5.7)]. Drug Interactions: increased international normalized ratio (INR), sometimes associated with bleeding, with concomitant warfarin use [see Drug Interactions (7.2)]. Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death [see Indications and Usage (1.2) and Warnings and Precautions (5.2)]. Neurologic: dysgeusia; somnolence Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant and kidney transplant dysfunction [see Warnings and Precautions (5.4)]. Skin and Subcutaneous Tissue Disorders: alopecia 7 DRUG INTERACTIONS 7.1 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 (12.3)]. In patients with type 2 diabetes, BYDUREON did not affect the absorption of orally administered acetaminophen to any clinically relevant degree. 7.2 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 (12.3)]. There have been postmarketing reports for BYETTA of increased INR with concomitant use of warfarin, sometimes associated with bleeding [see Adverse Reactions (6.4)]. 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. 8 USE IN SPECIFIC POPULATIONS 8.1 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 with 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 recommended dose of 2 mg/week, based on area under the time-concentration curve (AUC) [see Nonclinical Toxicology (13.3)]. 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 (13.3)]. 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 (13.3)]. 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 (13.3)]. 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. 8.3 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. 8.4 Pediatric Use Safety and effectiveness of BYDUREON have not been established in pediatric patients. BYDUREON is not recommended for use in pediatric patients. 8.5 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. 8.6 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 (5.4) and Clinical Pharmacology (12.3)]. 8.7 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 (12.3)]. 10 OVERDOSAGE 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. 11 DESCRIPTION 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 C184H282N50O60S 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-Val-Arg-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 hydroxide may be added during manufacture of BYDUREON Pen for pH adjustment. 12 CLINICAL PHARMACOLOGY 12.1 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. BYDUREON 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 is a GLP-1 receptor agonist that 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. 12.2 Pharmacodynamics Exenatide 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 The effect of exenatide infusion on glucose-dependent insulin secretion rates (ISR) was investigated in 11 healthy subjects. In these healthy subjects, on average, the ISR response was glucose-dependent (Figure 1). Exenatide did not impair the normal glucagon response to hypoglycemia. Figure 1: Mean (SE) Insulin Secretion Rates During Infusion of Exenatide or Placebo by Treatment, Time, and Glycemic Condition in Healthy Subjects
Note: mean change is least squares mean change. Note: The primary efficacy analysis was adjusted for multiple comparisons and a two-sided 98.3% confidence interval was utilized to assess difference between treatments. Note: HbA1c change data at 26 weeks were available from 86%, 87%, 85%, and 82% of the randomized subjects in the BYDUREON, metformin, sitagliptin, and pioglitazone groups, respectively. QW = once weekly. Least squares means were obtained using a mixed model repeated measure analysis with treatment, pooled country, visit, baseline HbA1c value, and treatment by visit interaction as fixed effects, and subject as a random effect. p<0.001, treatment vs comparator. The proportion of patients with a week 26 value achieving HbA1c of less than 7% at week 26 were 56%, 52%, 40%, and 55% for BYDUREON, metformin, sitagliptin, and pioglitazone, respectively. Patients who did achieve and HbA1c goal <7% and discontinued before week 26 were not included as responders. The mean changes from baseline to week 26 for fasting serum glucose were -41 mg/dL, -36 mg/dL, -20 mg/dL and -46 mg/dL, and for body weight were -2.0 kg, -2.0 kg, ‑0.8 kg and +1.5 kg for BYDUREON, metformin, sitagliptin, and pioglitazone, respectively. 14.2 Combination Therapy BYDUREON versus Sitagliptin and Pioglitazone, All as Add-on to Metformin Therapy A 26-week double-blind comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to sitagliptin and pioglitazone in patients with type 2 diabetes whose glycemic control was inadequate with metformin therapy. A total of 491 patients were studied 168 (34.2%) were Caucasian, 143 (29.1%) were Hispanic, 119 (24.2%) were Asian, 52 (10.6%) were Black, 3 (0.6%) were Native American, and 6 (1.2%) were classified otherwise. The mean baseline HbA1c was 8.5%. Patients were randomly assigned to receive BYDUREON 2 mg once every 7 days (weekly), sitagliptin 100 mg/day or pioglitazone 45 mg/day, in addition to their existing metformin therapy. The primary endpoint was change in HbA1c from baseline to week 26 (or the last value at time of early discontinuation). In this study, treatment with BYDUREON 2 mg QW resulted in a statistically significant mean HbA1c reduction compared to sitagliptin 100 mg/day. There was a numerically greater reduction in HbA1c with BYDUREON compared to pioglitazone, but there was not sufficient evidence to conclude superiority of BYDUREON 2 mg QW to pioglitazone 45 mg/day in reducing HbA1c after 26 weeks of treatment. Results for the primary endpoint at 26 weeks are summarized in Table 5.
Note: mean change is least squares mean change. QW = once weekly. Least squares means were obtained using an ANCOVA model with treatment, baseline HbA1c stratum, and country as fixed effects. Missing week 26 data (28%, 18%, and 24% for the BYDUREON, sitagliptin, and pioglitazone groups, respectively) were imputed by the LOCF technique. The proportion of patients with a week 26 value achieving HbA1c of less than 7% at week 26 were 46%, 30%, and 39% for BYDUREON, sitagliptin, and pioglitazone, respectively. Patients who did achieve an HbA1c goal <7% and discontinued before week 26 were not included as responders. The mean changes from baseline to week 26 for fasting serum glucose were -32 mg/dL, -16 mg/dL and -27 mg/dL, and for body weight were -2.3 kg, -0.8 kg and +2.8 kg for BYDUREON, sitagliptin, and pioglitazone, respectively. BYDUREON versus Insulin Glargine, Both as Add-on to Metformin or Metformin + Sulfonylurea Therapy A 26-week open-label comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to titrated insulin glargine in patients with type 2 diabetes whose glycemic control was inadequate with metformin or metformin plus sulfonylurea therapy. A total of 456 patients were studied: 379 (83.1%) were Caucasian, 47 (10.3%) were Hispanic, 25 (5.5%) were East Asian, 3 (0.7%) were Black, and 2 (0.4%) were West Asian. Background therapy was either metformin (70%) or metformin plus sulfonylurea (30%). The mean baseline HbA1c was 8.3%. Patients were randomly assigned to receive BYDUREON 2 mg once every 7 days (weekly) or insulin glargine once daily in addition to their existing oral antidiabetic therapy. 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. At week 26, 21% of insulin glargine treated patients were at fasting glucose goal. The primary endpoint was change in HbA1c from baseline to week 26 (or the last value at time of early discontinuation). Treatment with BYDUREON once weekly resulted in a mean reduction in HbA1c from baseline at 26 weeks of -1.5%. The mean reduction in HbA1c seen in insulin glargine arm at 26 weeks was -1.3%. The difference in observed effect size between BYDUREON and glargine in this trial excluded the pre-specified non-inferiority margin of +0.3%. The proportion of patients with a week 26 value achieving HbA1c of less than 7% at week 26 were 57% and 48% for BYDUREON and insulin glargine, respectively. Patients who did achieve an HbA1c goal <7% and discontinued before week 26 were not included as responders. The mean changes from baseline to week 26 for fasting serum glucose in this study were -38 mg/dL and -50 mg/dL, and for body weight were -2.6 kg and +1.4 kg for BYDUREON and insulin glargine, respectively. BYDUREON versus BYETTA, Both as Monotherapy or as Add-on to Metformin, a Sulfonylurea, a Thiazolidinedione, or Combination of Oral Agents A 24-week, randomized, open-label trial was conducted to compare the safety and efficacy of BYDUREON to BYETTA in patients with type 2 diabetes and inadequate glycemic control with diet and exercise alone or with oral antidiabetic therapy, including metformin, a sulfonylurea, a thiazolidinedione, or combination of two of those therapies. A total of 252 patients were studied: 149 (59%) were Caucasian, 78 (31%) Hispanic, 15 (6%) Black, and 10 (4%) Asian. Patients were treated with diet and exercise alone (19%), a single oral antidiabetic agent (47%), or combination therapy of oral antidiabetic agents (35%). The mean baseline HbA1c was 8.4%. Patients were randomly assigned to receive BYDUREON 2 mg once every 7 days (weekly) or BYETTA (10 mcg twice daily), in addition to existing oral antidiabetic agents. Patients assigned to BYETTA initiated treatment with 5 mcg twice daily then increased the dose to 10 mcg twice daily after 4 weeks. The primary endpoint was change in HbA1c from baseline to week 24 (or the last value at time of early discontinuation). Treatment with BYDUREON 2 mg QW resulted in a statistically significantly greater mean HbA1c reduction compared to BYETTA 10 mcg twice daily. Change in body weight was a secondary endpoint. Twenty-four week study results are summarized in Table 6.
Note: mean change is least squares mean change. QW = once weekly. BYETTA 5 mcg twice daily before the morning and evening meals for 4 weeks followed by 10 mcg twice daily for 20 weeks. Least squares (LS) means are adjusted for baseline HbA1c strata, background antihyperglycemic therapy, and baseline value of the dependent variable (if applicable). p<0.001, treatment vs comparator. Reductions from mean baseline (97/94 kg) in body weight were observed in both BYDUREON (−2.3 kg) and BYETTA (−1.4 kg) treatment groups. BYDUREON versus Liraglutide, Both as Add-on to Metformin, a Sulfonylurea, Metformin + Sulfonylurea, or Metformin + Pioglitazone Therapy A 26-week open-label comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to liraglutide in patients with type 2 diabetes whose glycemic control was inadequate with metformin, a sulfonylurea, metformin plus sulfonylurea, or metformin plus pioglitazone therapy. A total of 911 patients were studied: 753 (82.7%) were Caucasian, 111 (12.2%) were Asian, 32 (3.5%) were American Indian or Alaska Native, 8 (0.9%) were Black, 6 (0.7%) were multiple races, and 1 (0.1%) was Pacific Islander. Background therapy was either a single oral antidiabetic agent (35%) or a combination of oral antidiabetic agents (65%). The mean baseline HbA1c was 8.4%. Patients were randomly assigned to receive BYDUREON 2 mg once every 7 days (weekly) or liraglutide uptitrated from 0.6 mg/day to 1.2 mg/day, then 1.8 mg/day in addition to their existing oral antidiabetic therapy. Each titration was to be completed after at least one week, but could be delayed if the patient had severe nausea or vomiting as established by the investigator. Patients not tolerating the 1.8 mg/day dose of liraglutide by week 4 were discontinued from the study. The primary endpoint was change in HbA1c from baseline to week 26 (or the last value at time of early discontinuation). Treatment with BYDUREON once weekly resulted in a mean reduction in HbA1c from baseline at 26 weeks of -1.3%. The mean reduction in HbA1c seen in the liraglutide arm at 26 weeks was -1.5%. The HbA1c reduction with BYDUREON did not meet predefined non-inferiority criteria compared to liraglutide 1.8 mg/day. The non-inferiority margin was set at +0.25% in this study. Results for the primary endpoint at 26 weeks are summarized in Table 7.
Note: mean change is least squares mean change. Note: HbA1c change data at 26 weeks were available from 85% and 86% of the randomized subjects in the BYDUREON and liraglutide groups, respectively. QW = once weekly. Least squares means were obtained using a mixed model repeated measure analysis with treatment, country, OAD stratum, baseline HbA1c stratum, visit, baseline HbA1c, and treatment by visit interaction as fixed effects, and subject as a random effect. The proportion of patients with a week 26 value achieving HbA1c of less than 7% at week 26 were 48% and 56% for BYDUREON and liraglutide, respectively. Patients who did achieve an HbA1c goal <7% and discontinued before week 26 were not included as responders. The mean changes from baseline to week 26 for fasting serum glucose were -32 mg/dL and -38 mg/dL, and for body weight were -27 kg and -3.6 kg for BYDUREON and liraglutide, respectively. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 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 0310-6520-04). 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. 16.2 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. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=71fe88be-b4e6-4c2d-9cc3-8b1864467776
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