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Biopharmaceuticals Drug Delivery Endocrinology FDA

 News Release - March 3, 2014

U.S. FDA Approves Bydureon(R) Pen (exenatide extended-release for injectable suspension) for Once-Weekly Treatment of Adults with Type 2 Diabetes

WILMINGTON, Del.--(Healthcare Sales & Marketing Network)--AstraZeneca (AZN) today announced that the U.S. Food and Drug Administration (FDA) has approved the Bydureon® Pen (exenatide extended-release for injectable suspension) 2 mg as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Bydureon should not be used for treatment of patients with type 1 diabetes or diabetic ketoacidosis. 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. The concurrent use of Bydureon with insulin has not been studied and is not recommended.

Bydureon is the first and only once-weekly medicine for adults with type 2 diabetes. The Bydureon Pen is a pre-filled, single-use pen injector, eliminating the need for the patient to transfer the medication between a vial and syringe during the self-injection process. The Bydureon Pen contains the same formulation and dose as the original Bydureon single-dose tray, providing the same continuous release of exenatide. Bydureon has been shown to provide powerful HbA1c (blood glucose level) reduction. In a 24-week, randomized, open-label trial, once-weekly Bydureon demonstrated an HbA1c reduction of 1.6 percentage points vs 0.9 percentage points for twice-daily Byetta® (exenatide) injection at 24 weeks (baseline HbA1c 8.5% and 8.4%, respectively). Additionally, Bydureon demonstrated a mean weight reduction of 5.1 pounds (2.3 kg) vs 3.1 pounds (1.4 kg) with Byetta (baseline 213.8 pounds [97 kg] and 207.2 pounds [94 kg], respectively). Bydureon is not indicated for the management of obesity, and weight change was a secondary endpoint in clinical trials.

The Prescribing Information for Bydureon includes a Boxed Warning regarding the risk of thyroid C-cell tumors. 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, in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), or history of a serious hypersensitivity reaction to exenatide.

Based on post-marketing data, exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, Bydureon should be discontinued promptly and not restarted if pancreatitis is confirmed. Other antidiabetic therapies should be considered in patients with a history of pancreatitis. Bydureon and Byetta contain the same active ingredient and should not be used together.

“We are pleased to receive approval for the Bydureon Pen, which can provide a powerful reduction in blood glucose levels along with the potential benefit of weight loss, through a once-weekly dose in a pre-filled device,” said Briggs Morrison, M.D., executive vice president, Global Medicines Development and chief medical officer, AstraZeneca. “We are committed to addressing the needs of adults with type 2 diabetes, including ongoing research to develop new treatments and methods of delivery.”

The Bydureon Pen delivers exenatide via microsphere technology in a once-weekly dose requiring no titration. It can be administered at any time of the day, with or without meals. Prior to initiation of the Bydureon Pen, patients should be trained by their healthcare professional.

AstraZeneca plans to make the Bydureon Pen available for patients later this year. The Bydureon single-dose tray will remain on the market for patients prescribed Bydureon.

About Bydureon® Clinical Development Program

The FDA approval of Bydureon was based on the safety and efficacy data from the pivotal DURATION-5 clinical trial, in which treatment with Bydureon resulted in improvements in glycemic control. The DURATION-5 trial was a randomized open-label clinical study of 252 adult 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 a combination of two of these oral type 2 diabetes medications comparing Bydureon to Byetta (n = 129 and n = 123, respectively). After 24 weeks of treatment, patients taking once-weekly Bydureon experienced a statistically significant mean reduction in HbA1c of 1.6 percentage points (8.5% baseline), compared to a reduction of 0.9 percentage points (8.4% baseline) for patients taking Byetta.HbA1c is a measure of average blood sugar over three months. Both treatment groups achieved a reduction in weight by the end of the study, with an average loss of 5.1 pounds or 2.3 kg (213.8 pounds or 97 kg baseline) for patients taking Bydureon and 3.1 pounds or 1.4 kg (207.2 pounds or 94 kg baseline) for patients taking Byetta (change in weight was a secondary endpoint).The most frequently reported adverse event in both groups was nausea, reported less frequently by Bydureon users (14%) than by Byetta users (35%). Other common treatment-emergent adverse events in the Bydureon group included diarrhea (9.3% vs 4.1%) and injection-site erythema (5.4% vs 2.4%, respectively). There were no major hypoglycemic events in either treatment arm.Minor episodes of hypoglycemia occurred in Bydureon 2 mg and Byetta 10 mcg patients with concomitant sulfonylurea use (12.5% vs 11.8%, respectively).

The FDA approval for Bydureon was received in 2012. Bydureon is currently available in 42 countries worldwide, including European Union countries.

(exenatide extended-release for injectable suspension)

Indication and Important Limitations of Use for BYDUREON:

BYDUREON is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

  • Because of the uncertain relevance of the rat thyroid C-cell tumor findings to humans, prescribe only to patients for whom potential benefits are considered to outweigh potential risk.

  • Not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise.

  • Not a substitute for insulin, should not be used in patients with type 1 diabetes or diabetic ketoacidosis, and cannot be recommended for use with insulin.

  • BYDUREON and BYETTA® (exenatide) injection both contain the same active ingredient, exenatide, and should not be used together.

  • Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, based on postmarketing data. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using BYDUREON; consider other antidiabetic therapies for these patients.

Important Safety Information for BYDUREON:


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.


Patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

Patients with prior serious hypersensitivity reactions to exenatide or to any of the product components.

Warnings and Precautions

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 pancreatitis (persistent severe abdominal pain, sometimes radiating to the back, with or without vomiting). If pancreatitis is suspected, BYDUREON should be discontinued promptly and should not be restarted if pancreatitis is confirmed.

Hypoglycemia: Increased risk of hypoglycemia when used in combination with a sulfonylurea (SFU). Clinicians may consider reducing the SFU dose to minimize risk of hypoglycemia. It is possible that use of BYDUREON with other glucose-independent insulin secretagogues (eg, meglitinides) could increase the risk of hypoglycemia.

Renal Impairment: Should not be used in patients with severe renal impairment or end-stage renal disease. Use with caution in patients with renal transplantation or moderate renal failure. 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 and kidney transplantation.

Gastrointestinal Disease: Because exenatide is commonly associated with gastrointestinal adverse reactions, BYDUREON is not recommended in patients with severe gastrointestinal disease (eg, gastroparesis).

Immunogenicity: Patients may develop antibodies to exenatide. In 5 registration trials, attenuated glycemic response was associated in 6% of BYDUREON-treated patients with antibody formation. If worsening of or failure to achieve adequate glycemic control occurs, consider alternative antidiabetic therapy.

Hypersensitivity: Postmarketing reports of serious hypersensitivity reactions (eg, anaphylaxis and angioedema). If this occurs, patients should discontinue BYDUREON and other suspect medications and promptly seek medical advice.

Macrovascular Outcomes: No clinical studies establishing conclusive evidence of macrovascular risk reduction with BYDUREON or any other antidiabetic drug.


In 5 comparator-controlled, 24- to 30-week BYDUREON trials, the incidence of withdrawal due to adverse events was 4.9% for BYDUREON, 4.9% for BYETTA, and 2.0% for other comparators. The most common adverse reactions leading to withdrawal for BYDUREON, BYETTA, and comparators respectively were nausea (0.5%, 1.5%, 0.3%), injection-site nodule (0.5%, 0.0%, 0.0%), diarrhea (0.3%, 0.4%, 0.3%), injection-site reaction (0.2%, 0.0%, 0.0%), and headache (0.2%, 0.0%, 0.0%). One percent of BYDUREON patients withdrew due to injection-site adverse reactions.

Most Common Adverse Reactions (?5%)


24-week trial: nausea (14% vs 35%), diarrhea (9.3% vs 4.1%), injection-site erythema (5.4% vs 2.4%).

30-week trial: nausea (27% vs 33.8%), diarrhea (16.2% vs 12.4%), vomiting (10.8% vs 18.6%), injection-site pruritus (18.2% vs 1.4%), constipation (10.1% vs 6.2%), gastroenteritis viral (8.8% vs 5.5%), gastroesophageal reflux disease (7.4% vs 4.1%), dyspepsia (7.4% vs 2.1%), injection-site erythema (7.4% vs 0.0%), fatigue (6.1% vs 3.4%), headache (6.1% vs 4.8%), injection-site hematoma (5.4% vs 11.0%).

BYDUREON vs titrated insulin glargine: nausea (12.9% vs 1.3%), headache (9.9% vs 7.6%), diarrhea (9.4% vs 4.0%), injection-site nodule (6.0% vs 0.0%).

Combination trial vs sitagliptin and pioglitazone: nausea (24.4% vs 9.6% and 4.8%), diarrhea (20.0% vs 9.6% and 7.3%), vomiting (11.3% vs 2.4% and 3.0%), headache (9.4% vs 9.0% and 5.5%), constipation (6.3% vs 3.6% and 1.2%), fatigue (5.6% vs 0.6% and 3.0%), dyspepsia (5.0% vs 3.6% and 2.4%), decreased appetite (5.0% vs 1.2% and 0.0%), injection-site pruritus (5.0% vs 4.8% and 1.2%).

Monotherapy trial vs sitagliptin, pioglitazone, and metformin: nausea (11.3% vs 3.7%, 4.3%, and 6.9%), diarrhea (10.9% vs 5.5%, 3.7%, and 12.6%), injection-site nodule (10.5% vs 6.7%, 3.7%, and 10.2%), constipation (8.5% vs 2.5%, 1.8%, and 3.3%), headache (8.1% vs 9.2%, 8.0%, and 12.2%), dyspepsia (7.3% vs 1.8%, 4.9%, and 3.3%).

Hypoglycemia: No major hypoglycemia was reported for BYDUREON- or comparator-treated patients in five 24- to 30-week trials. Minor hypoglycemia incidences for BYDUREON vs comparator-treated patients were as follows: 24-week trial vs BYETTA: with SFU, 12.5% vs 11.8%; without SFU, 0.0% for both; 30-week trial vs BYETTA: with SFU, 14.5% vs 15.4%; without SFU, 0.0% vs 1.1%; monotherapy trial vs sitagliptin, pioglitazone, and metformin: 2.0% vs 0.0% (all comparators); combination trial vs sitagliptin and pioglitazone: 1.3% vs 3.0% and 1.2%; vs titrated insulin glargine, with SFU, 20.0% vs 43.9%; without SFU, 3.7% vs 19.1%.

Injection-site reactions were observed more frequently in BYDUREON-treated patients (17.1%) vs patients treated with BYETTA (12.7%), titrated insulin glargine (1.8%), or placebo injection (6.4%-13.0%). Injection-site reactions were observed in 14.2% of antibody-positive patients vs 3.1% of antibody-negative patients, with higher incidence in those with higher-titer antibodies. BYETTA-treated patients had similar incidence between antibody-positive and antibody-negative patients (5.8% vs 7.0%). Small, asymptomatic, subcutaneous injection-site nodules are seen with the use of BYDUREON.

Drug Interactions

Oral Medications: BYDUREON slows gastric emptying and can reduce the rate of absorption of orally administered drugs. Use with caution with oral medications.

Warfarin: Postmarketing reports with exenatide of increased international normalized ratio (INR) sometimes associated with bleeding with concomitant use of warfarin. Monitor INR frequently until stable upon initiation or alteration of BYDUREON.

Use in Specific Populations

Pregnant and Nursing Women: Based on animal data, BYDUREON may cause fetal harm and should be used 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. When administered to a nursing woman, a decision should be made whether to discontinue nursing or to discontinue BYDUREON.

Pediatric Patients: Use in pediatric patients is not recommended as safety and effectiveness have not been established.

Please click here for US Full Prescribing Information for BYDUREON (exenatide extended-release for injectable suspension) 2 mg, including Boxed WARNING regarding risk of thyroid C-cell tumors, and click here for Medication Guide.

About GLP-1 Receptor Agonists

An agonist is a molecule, such as a drug or a hormone, which binds to a receptor of a cell and triggers a response by that cell. A glucagon-like peptide-1 (GLP-1) receptor agonist binds to and activates the GLP-1 receptor, which exhibits multiple anti-hyperglycemic actions.

About Type 2 Diabetes

Diabetes is estimated to affect 25.8 million people in the U.S. and more than 382 million people worldwide. The prevalence of diabetes is projected to reach more than 592 million people worldwide by 2035. Type 2 diabetes accounts for approximately 90-95 percent of all cases of diagnosed diabetes. Type 2 diabetes is a chronic disease characterized by pathophysiologic defects leading to elevated glucose levels. Over time, this sustained hyperglycemia contributes to further progression of the disease. Significant unmet needs still exist, as many patients remain inadequately controlled on their current glucose-lowering regimen.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit:

Source: AstraZeneca

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