Dosage Form: injection
FULL PRESCRIBING INFORMATION
Exenatide extended-release causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats compared to controls. It is unknown whether Bydureon causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be determined by clinical or nonclinical studies. Bydureon is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Routine serum calcitonin or thyroid ultrasound monitoring is of uncertain value in patients treated with Bydureon. Patients should be counseled regarding the risk and symptoms of thyroid tumors [see Contraindications (4.1), Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)].
Indications and Usage for Bydureon
Bydureon is an extended-release formulation of exenatide, administered as an injection once every seven 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 in multiple clinical settings [see Clinical Studies (14)].
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 pancreatitis while using Bydureon. Other antidiabetic therapies should be considered in patients with a history of pancreatitis.
Bydureon Dosage and Administration
Recommended Dosing
Bydureon (2 mg per dose) should be administered once every seven 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 three days later. Thereafter, patients can resume their usual dosing schedule of once every seven days (weekly).
If a dose is missed and the next regularly scheduled dose is due one or two 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 is intended for patient self-administration. Bydureon is provided in a single-dose tray containing: one vial of 2 mg exenatide, one vial connector, one prefilled diluent syringe and two needles (one provided as a spare) [see How Supplied/Storage and Handling (16.1)]. Do not substitute needles or any other components in the tray.
Bydureon must be injected immediately after the powder is suspended in the diluent and transferred to the syringe. 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.
See the Bydureon 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 two weeks) elevations in blood glucose concentrations.
Dosage Forms and Strengths
Bydureon is 2 mg exenatide extended-release for injectable suspension for subcutaneous administration once every seven days (weekly).
Contraindications
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.
Warnings and Precautions
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 could not be determined by clinical or nonclinical studies. Serum calcitonin was not assessed in the clinical trials supporting the approval of Bydureon [see Boxed Warning, Contraindications (4.1)].
Serum calcitonin is a biological marker of MTC. Patients with MTC usually have calcitonin values >50 ng/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 Counseling Information (17)].
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 Mechanism of Action (12.1).
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 to 50 mL/min) [see Use in Specific Populations (8.6) 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.
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 24-30 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)].
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 (6.2)].
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Bydureon or any other antidiabetic drug.
Adverse Reactions
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 seven 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 seven 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 seven 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 seven 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 24-30 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 24-30 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.
| Abbreviations: N = The number of intent-to-treat patients | |
| Note: Percentages are based on the number of intent-to-treat patients in each treatment group. | |
| |
| 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) |
There were no reported events of major hypoglycemia in these five comparator-controlled 24-30 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 (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.
Other Adverse Reactions
Bydureon
Tables 2 and 3 summarize adverse reactions with an incidence ≥5% reported in the five comparator controlled 24-30 week trials of Bydureon used as monotherapy or as add-on to metformin, a sulfonylurea, a thiazolidinedione or combination of these oral antidiabetic agents.
| 26-Week Monotherapy Trial | ||||
|---|---|---|---|---|
| Bydureon 2 mg N = 248 % | Sitagliptin 100 mg N = 163 % | Pioglitazone 45 mg N = 163 % | Metformin 2000 mg N = 246 % | |
| N = The number of intent-to-treat patients. | ||||
| Note: Percentages are based on the number of intent-to-treat patients in each treatment group. | ||||
| ||||
| 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 = The number of intent-to-treat patients. | |||
| Note: Percentages are based on the number of intent-to-treat patients in each treatment group. | |||
| |||
| 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 | |
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 24-30 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).
Small, asymptomatic subcutaneous injection site nodules are seen 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 one 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 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.
Post-Marketing Experience
BYETTA
The following additional adverse reactions have been reported during post-approval 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 Limitations of Use (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
Drug Interactions
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.
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 (6.2)]. 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.
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 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 2-4 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
Amylin Pharmaceuticals, Inc. maintains a Pregnancy Registry to monitor pregnancy outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling (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 24-30 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 to 50 mL/min) [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].
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)].
Overdosage
There were no reports of overdose in the five comparator-controlled 24-30 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.
Bydureon Description
Bydureon (exenatide extended-release for injectable suspension) is supplied as a sterile powder to be suspended in the diluent included in the single-dose tray 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. Exenatide is incorporated in an extended release microsphere formulation containing the 50:50 poly(D,L-lactide-co-glycolide) polymer (37.2 mg per vial) along with sucrose (0.8 mg per vial). The powder must be suspended in the diluent prior to injection. The diluent is provided in a prefilled syringe. Each prefilled syringe delivers 0.65 mL of the diluent as a clear, colorless to pale yellow solution composed of carboxymethylcellulose sodium (23 mg), polysorbate 20 (0.77 mg), sodium phosphate monobasic monohydrate (0.74 mg), sodium phosphate dibasic heptahydrate (0.62 mg), sodium chloride (5.0 mg), and water for injection.
Bydureon - Clinical Pharmacology
Mechanism of Action
Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. 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.
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.
SE = standard error.
Notes: 5 mmol = 90mg/dL, 4 mmol/L = 72 mg/dL, 3.2 mmol/L = 58 mg/dL; Study medication infusion was started at time = 0 min.
Statistical assessments were for the last 30 min of each glycemic step, during which the target glucose concentrations were maintained.
*p <0.05, exenatide treatment relative to placebo.
Figure 1: Mean (SE) Insulin Secretion Rates During Infusion of Exenatide or Placebo by Treatment, Time, and Glycemic Condition in Healthy Subjects
Glucagon secretion: In patients with type 2 diabetes, exenatide moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia.
Gastric emptying: Exenatide slows gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation.
Food intake: Infusion of exenatide in eight healthy subjects resulted in a 19% decrease in caloric intake following an ad libitum meal.
Fasting and Postprandial Glucose
In a separate 15-week controlled study, where fasting glucose was assessed on a weekly basis, Bydureon treatment resulted in a mean reduction in fasting glucose of 17 mg/dL following two weeks of therapy with full effect on fasting
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