Amylin announced the FDA’s rejection of their new Byetta formulation on Monday. The proposed drug, Bydureon, would allow users to take one dose a week to regulate their diabetes, as opposed to Byetta, which is a twice-daily injection. Bydureon has also been commonly referred to as Byetta LAR.

While the FDA has not asked for lengthy additional clinical trials, which would delay release of the drug significantly, Amylin officials say the agency sent the company a letter indicating that they need to provide finalized information for what will be on the new drug’s label, a risk evaluation and mitigation strategy (REMS) for reducing the health risks to users, and clarification on the manufacturing processes for the medication.

Last week the FDA released an inspection report about problems at the Byetta manufacturing plant in Ohio, which cited a number of quality control and staff training issues. Among problems found at the plant, FDA inspectors said that raw materials used to make Byetta were not properly inspected coming into the plant, and workers in a variety of positions have not been properly trained to ensure quality control.

Byetta (exenatide) is a type 2 diabetes drug that is manufactured and distributed jointly by Amylin and Eli Lilly & Co. The drug is used to control blood sugar levels and is part of a class of medications known as incretin mimetics, which imitate natural hormones that lower blood glucose levels.

In November, the FDA issued a warning indicating that they had received at least 78 post-marketing reports which raised concerns about Byetta kidney problems, with 62 of those reports involving users experiencing kidney failure. The alert followed FDA warnings issued in October 2007 and August 2008 of reports involving cases of pancreatitis with Byetta, including severe reports of hemorrhagic pancreatitis and necrotizing pancreatitis, which can be fatal.

In cases where a drug that is deemed important to patients also causes serious health problems, the FDA can require a REMS report that details how the drug maker intends to provide the drug in a way that reduces risk to patients as much as possible.

Amylin and Eli Lilly also currently face a number of Byetta lawsuits involving allegations that the drug makers failed to adequately warn about the risk of pancreatitis and kidney failure.

According to an FDA inspection report (pdf) released last week, raw materials used to make Byetta were not properly inspected coming into the plant, and workers in a variety of positions at the West Chester plant, near Cincinnati, Ohio, have not been properly trained to ensure quality control.

Byetta is a type 2 diabetes drug that is manufactured and distributed jointly by Amylin and Eli Lilly & Co. The drug is used to control blood sugar levels and is part of a class of medications known as incretin mimetics, which imitate natural hormones that lower blood glucose levels. The drug makers are currently seeking approval for a new long-acting formulation of the drug, which would allow users to take one injection per week, instead of the current twice-daily dosing regimen. A decision on the drug approval is expected this week.

According to the FDA’s inspection report, the plant failed to establish or follow procedures designed to prevent contamination of drug products that are supposed to be sterile. The plant also failed to test in-process materials properly for quality and purity, and did not follow up on investigations into unexplained discrepancies and failures of batches of drugs.

The inspection report follows an FDA warning issued in January about off-label promotional statements for Byetta at a conference in June.

The production issues also add to recent concerns about potential health problems with Byetta, which has been linked to a risk of kidney failure and pancreatitis. In November, the FDA issued a new warning indicating that they have received at least 78 post-marketing reports that link Byetta kidney problems, including 62 cases where the users experienced kidney failure. And in October 2007 and August 2008, the FDA issued safety alerts about reports of Byetta pancreatitis cases, including severe reports of hemorrhagic pancreatitis and necrotizing pancreatitis, which can be fatal.

Amylin and Eli Lilly also currently face a number of Byetta lawsuits involving allegations that the drug makers failed to adequately warn about the risk of pancreatitis and kidney failure.

The FDA letters were sent to Amylin Pharmaceuticals, Eli Lilly and Co., Bayer Healthcare Pharmaceuticals and Cephalon, alerting the companies that federal regulators were aware of statements made by representatives that provided misleading or false information about the benefits of their products. In some cases, the companies also promoted their drugs for uses not approved by the FDA.

In a letter to Amylin Pharmaceuticals regarding Byetta (exenatide) , the agency said that representatives speaking at the Endocrine Society’s Annual Meeting (ENDO) in June promoted the drug for off-label uses, saying that it could be used as a stand-alone diabetes treatment, when Byetta was only approved at the time for use with other diabetes medications. Since that time, Byetta has been approved for solo use. The letter also says that representatives exaggerated the potential weight loss benefits of Byetta, and overstated its efficacy.

Byetta is a type 2 diabetes drug that is used to control blood sugar levels. It is part of a class of medications known as incretin mimetics, which imitate natural hormones that lower blood glucose levels.

The letter is just the latest problem for the drug maker. In November, the FDA issued a new warning indicating that they have received at least 78 post-marketing reports that link Byetta side effects to kidney problems, including 62 cases where the users experienced kidney failure. And in October 2007 and August 2008, the FDA issued safety alerts about reports of Byetta pancreatitis problems, including severe cases of hemorrhagic pancreatitis and necrotizing pancreatitis, which can be fatal. Symptoms of pancreatitis, which is an inflammation of the pancreas, include nausea, vomiting, severe pain in the upper abdomen and back, a rise or fall in blood pressure, and increased heart or respiratory rates.

The FDA letter to Eli Lilly was sent over their antipsychotic Cymbalta (duloxeitine hydrochloride), citing the company for direct-to-consumer print advertisements that made false or misleading claims about the drug’s effectiveness while failing to note any Cymbalta health risks in the main ad. The health risk information was on an adjacent page in a way that appeared unconnected to the main advertisement, FDA regulators noted.

The warning letter regarding Bayer’s contraceptive intrauterine device (IUD) Mirena (levonorgestrel) claims that the company overstated the drug’s effectiveness, made unsubstantiated claims and minimized the risks in a live consumer-directed program, where representatives travel to consumers’ homes.

Bayer has run into trouble in the past with the FDA over marketing claims involving its contraceptive products. In late 2008, the FDA and several state attorney generals forced Bayer to run a $20 million corrective advertising campaign for its Yaz birth control pills because prior marketing contained false claims about the drug’s acne and PMS-fighting benefits, and did not clearly state all of the known Yaz side effects, drowning some of them out with loud music. As a result of the misleading advertisements, Bayer agreed that the FDA will screen future Yaz ads for six years before they can be aired.

A fourth letter targeted at Cephalon’s leukemia medication Treanda (bendamustine hydrochloride), citing problems with pocket dosing cards that omit information on Treanda health risks and dosing information.

All of the companies have been warned to immediately cease any false or misleading advertisements and have been ordered to explain whether they intend to comply with the request and how or why they believe the false and misleading drug advertisement claims are incorrect.

The Byetta lawsuit was filed in Duval County Court in Florida by Shadim Salem, the widow of Fred J. Salem, who died in January 2008, about six months after he started receiving Byetta injections according to a report by Courthouse News Service. Shadim Salem has accused Byetta’s manufacturers of negligence, failure to warn, and breach of warranty, saying the diabetes drug caused both liver and pancreatic cancer in her husband.

Byetta (exenatide) is a type 2 diabetes drug that is used to control blood sugar levels. It is part of a class of medications known as incretin mimetics, which imitate natural hormones that lower blood glucose levels. Last month, the FDA expanded the use of Byetta to a stand-alone diabetes treatment, but insisted that warnings about the risk of pancreatitis from Byetta be added to the label and will require additional studies.

Salem’s lawsuit says that Byetta’s manufacturers overstated the drug’s benefits while downplaying its risks, including the risk of pancreatitis. She is seeking medical and funeral expenses, damages for loss of consortium and other damages.

In April 2009, Amylin dismissed a potential link between Byetta and cancer, after a similar diabetes drug in the same class of medications was linked to a potential risk of thyroid cancer.

Amylin and Eli Lilly already face a number of Byetta injury lawsuits involving allegations that the drug makers failed to adequately warn about the risk of pancreatitis and kidney failure from the diabetes drug.

Byetta (exenatide) is a type 2 diabetes drug that is used to control blood sugar levels. It is part of a class of medications known as incretin mimetics, which imitate natural hormones that lower blood glucose levels.

The FDA recently expanded the approval of Byetta for use as a standalone treatment, without use of other diabetes drugs. On October 30, Eli Lilly & Co. and Amylin Pharmaceuticals, Inc., which jointly market the drug, announced the new approval and indicated that warnings about the risk of pancreatitis from Byetta would be added to the label. However, they did not disclose that additional studies were being required to further examine the pancreatitis risk.

Citigroup analyst Yaron Werber informed investors last week that the FDA is also requiring additional post-marketing studies into the potential Byetta pancreatitis side effects and a Risk Evaluation and Mitigation Stategy (REMS), which would be used to ensure that the drug’s benefits outweigh the risks. The information was obtained from a copy of the FDA’s approval letter.

Concerns about the potential Byetta pancreatitis risk first surfaced in October 2007, when the FDA issued an alert indicating that the drug had been linked to at least 30 reports of acute pancreatitis. In August 2008, the FDA notified doctors about six more cases of severe pancreatitis from Byetta, including two deaths. Following the FDA announcement, the drug makers disclosed that they were aware of at least four other pancreatitis deaths among Byetta users.

According to the FDA approval letter [PDF] expanding Byetta as a standalone therapy, the FDA identified “new safety information” that they have become aware of since the drug was originally approved in April 2005, including postmarketing reports of acute pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, renal failure and thyroid neoplasms associated with side effects of Byetta.

“After considering this new safety information, we have determined that postmarketing requirements are needed to assess the risk of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, and the risk of thyroid neoplasms, and that a REMS is necessary for Byetta (exenatide) to ensure that the benefits of the drug outweigh the risks of acute pancreatitis and acute renal failure,” the FDA states in the letter.

On November 2, the FDA announced that new warnings would be added to the drug about the potential Byetta kidney side effects, indicating that the agency has received at least 78 post-marketing reports of users who developed altered kidney function, including 62 reports of kidney failure. The new warnings indicated doctors should watch for signs of kidney problems from Byetta, especially when starting treatment or increasing dosage in patients with moderate pre-existing kidney function issues.

Amylin and Eli Lilly already face a number of Byetta lawsuits involving allegations that the drug makers failed to adequately warn about the risk of pancreatitis and kidney failure from the diabetes drug.

Public Citizen issued the recommendation in the November 2009 issue of their Worst Pills, Best Pills Newsletter, which was first published days before the FDA indicated that nearly 80 adverse event reports have linked Byetta side effects to altered kidney function.

Byetta (exenatide) is a type 2 diabetes drug that was approved by the FDA in April 2005 to help control blood sugar levels. Public Citizen indicates that people should avoid using the drug for at least seven years after it was approved, indicating that Byetta was not sufficiently tested before being released to the public. The drug was approved after clinical trials on a small group of patients who only used only used the drug for short-term treatments of seven months, while patients are expected to take the drug for years.

“The studies that looked at exanatide were too short and too small to answer any questions about whether or not the drug improves the overall health or quality of life for patients with Type-2 diabetes,” states Public Citizen. “Exenatide has not been shown to reduce any meaningful endpoints, including, but not limited to, the risk of death, neuropathy, vision loss, heart disease or any of the other major complications of Type-2 diabetes.”

Public Citizen also raised concerns over potential side effects of Byetta that may emerge as more individuals use the type-2 diabetes drug. They pointed out two serious health problems that have already emerged since the drug was introduced, including a link to pancreatitis and reports of altered kidney function.

In October 2007 and August 2008, the FDA issued safety alerts about reports of Byetta pancreatitis problems, including severe cases of hemorrhagic pancreatitis and necrotizing pancreatitis, which can be fatal. Symptoms of pancreatitis, which is an inflammation of the pancreas, include nausea, vomiting, severe pain in the upper abdomen and back, a rise or fall in blood pressure, and increased heart or respiratory rates.

Following the FDA warnings, Public Citizen indicates that they conducted an independent analysis of the Byetta pancreatitis reports, finding a total of 181 reports of acute pancreatitis with Byetta between April 2005 and March 2009, including 142 cases that required hospitalization.

Public Citizen also expressed concerns over reports of kidney problems with Byetta, pointing out a warning issued in May 2008 by the European Medicines Agency, which is Europe’s drug regulatory agency, about 86 users of Byetta suffering kidney failure or indicators of kidney malfunction.

On Monday, the FDA issued a new warning indicating that they have received at least 78 post-marketing reports that link Byetta side effects to kidney problems, including 62 cases where the users experienced kidney failure. The U.S. regulatory agency determined that new information needs to be added to the drug’s label and that a patient Medication Guide needs to be developed to ensure patients and the medical community are aware of the risk and watch for signs of kidney problems with Byetta.

Following the FDA announcement, Amylin and Eli Lilly released a statement this week saying they agree with the labeling changes, but called the reported kidney problems rare events where there were usually other factors involved. The statement said that diabetes is a leading cause of kidney failure and that there is no evidence in Byetta’s preclinical and clinical studies that provide any evidence of Byetta having a toxic effect on the kidney.

Public Citizen generally recommends that people wait seven years before taking any new drug the FDA approves, noting that half of all new drug safety withdrawals occur within two year of FDA approval, and half of all “black box” warnings, the strongest label warning under federal law, are applied to drugs within the first seven years.

The agency indicates that at least 78 post-marketing reports have linked Byetta side effects to altered kidney function, including 62 reports of kidney failure.

The new labeling warns healthcare professionals to watch for signs of Byetta kidney problems, especially when starting treatment or increasing dosage in patients with moderate pre-existing kidney problems. The FDA indicates that some of the patients who reported Byetta kidney side effects had pre-existing kidney disease or increased risk factors for problems. The new labeling will also highlight that the drug should not be used in patients with severe renal impairment or end-stage kidney disease.

Byetta (exenatide) is a type 2 diabetes drug that is used to control blood sugar levels. It is part of a class of medications known as incretin mimetics, which imitate natural hormones that lower blood glucose levels. Byetta is manufactured by Amylin Pharmaceuticals and Eli Lilly & Co. The FDA reports that nearly 7 million prescriptions for Byetta were issued from April 2005 through September 2008.

The FDA indicates that the most common side effects from Byetta include nausea, vomiting and diarrhea, which could be a contributing factor to altered kidney function. Kidney failure on Byetta can lead to a build-up of waste products in the blood, which can result in serious illness or death.

“Health care professionals and patients taking Byetta should pay close attention to any signs or symptoms of kidney problems,” said Amy Egan, M.D. M.P.H., of the Division of Metabolism and Endocrinology Products at the FDA’s Center for Drug Evaluation and Research. “Patients also should be aware that problems with kidney function could lead to changes in urine color, frequency of urination or the amount of urine, unexplained swelling of the hands or feet, fatigue, changes in appetite or digestion, or dull ache in mid to lower back.”

In October 2007 and August 2008, the FDA issued a safety alerts about reports that linked Byetta side effects to pancreatitis, including severe cases of hemorrhagic pancreatitis and necrotizing pancreatitis, which can be fatal. Symptoms of pancreatitis, which is an inflammation of the pancreas, include nausea, vomiting, severe pain in the upper abdomen and back, a rise or fall in blood pressure, and increased heart or respiratory rates.

BYETTA LAWSUIT STATUS: Lawyers are evaluating potential Byetta pancreatitis lawsuits and Byetta kidney failure lawsuits for individuals who have experienced problems that may be caused by side effects of the diabetes drug.

>>REVIEW A CASE WITH A BYETTA LAWYER<<

MANUFACTURERS: Amylin Pharmaceuticals, Inc. and Eli Lilly & Co.

OVERVIEW: Byetta (exenatide) is a type 2 diabetes drug which was approved by the FDA in April 2005 to help reduce blood sugar levels. As of September 2008, more than 7 million prescriptions for Byetta have been filled.

The drug belongs to a class of drugs known as incretin mimetics, which mimic the action of endogenous incretin hormones like GIP and GLP-1, which are found in the gastrointestinal tract. Byetta lowers blood glucose levels by stimulating insulin secretion from pancreatic cells.

BYETTA KIDNEY SIDE EFFECTS: In November 2009, the FDA announced that new prescribing information would be added about reports of Byetta side effects linked to kidney failure and other kidney problems. At that time, the agency indicated that at least 78 reports have been received of users experiencing altered kidney function, including at least 62 reports of kidney failure on Byetta.

As a result of the post-marketing reports, the FDA notified healthcare providers and patients to watch for signs of Byetta kidney side effects, which could lead to:

• Changes in urine color
• Changes in frequency of urination or the amount of urine
• Unexplained swelling of the hands or feet
• Fatigue
• Changes in appetite or digestion
• Dull ache in the mid-to-low back

The most common side effects of Byetta include nausea, vomiting and diarrhea, which the FDA suggested could be a contributing factor in the reports of kidney problems with Byetta. This is a serious and potentially life-threatening issue, as altered kidney function could lead to a build-up of waste products in the blood and potentially result in serious injury or death.

BYETTA PANCREATITIS SIDE EFFECTS: In October 2007, the FDA issued an alert about an association between Byetta and pancreatitis, which could lead to fatal injuries for some users. At that time, the FDA had received at least 30 reports of acute pancreatitis associated with Byetta, and the manufacturer agreed to update the warning label about this potential Byetta side effect.

In August 2008, a second FDA alert was issued to inform healthcare providers about six additional cases of necrotizing pancreatitis or hemorrhagic pancreatitis which had been reported among Byetta users. At least two of these cases resulted in fatal injuries for the user.

Pancreatitis is an inflammation of the pancreas, which can cause symptoms like:

• Severe upper abdominal pain which may radiate through the back
• Nausea and Vomiting
• High or Low Blood Pressure
• Elevated Heart or Respiratory Rates

Hemorrhagic pancreatitis is a severe form of the condition where massive erosion of blood vessels can lead to severe bleeding.

Necrotizing pancreatitis involves tissue damage, which leads to the release of toxins and enzymes into the blood stream and may cause multi-organ failure and death.

The FDA has recommended that healthcare providers monitor their patients who are receiving Byetta and the drug should be stopped if pancreatitis is suspected. If someone develops pancreatitis or has a history of the condition, the FDA indicates that a different diabetes treatment should be used. Individuals receiving the drug have also been urged to report any potential Byetta side effects, including unexplained severe abdominal pain, either with or without bleeding.

At least 88 Janumet or Januvia pancreatitis reports were received by the FDA between October 2006 and February 2009, leading the agency to recommend that doctors monitor their patients carefully for signs of pancreatitis after starting treatment or increasing dosage. In addition, since the drugs have not been studied among individuals with a history of pancreatitis, they should be used with caution and appropriate monitoring for these patients.

Januvia and Janumet, which are both manufactured by Merck & Co., are newer drugs approved for the treatment of adults with Type-2 diabetes. They are the first in a new class of drugs known as dipeptidyl peptidase-4 (DPP-4) inhibitors.

Pancreatitis is an inflammation of the pancreas that can cause symptoms like severe upper abdominal pain which may radiate through the back, nausea, vomiting, high or low blood pressure, increased heart rates or elevated respiratory rates.

Among the reported Januvia pancreatitis cases described by the FDA were at least two cases of hemorrhagic or necrotizing pancreatitis, which are more severe and potentially life-threatening. Hemorrhagic pancreatitis involves massive erosion of blood vessels that can lead to severe bleeding. Necrotizing pancreatitis involves tissue damage, which leads to the release of toxins and enzymes into the blood stream and may cause multi-organ failure or death.

Of the 88 cases, 58 of the patients required hospitalization and four were treated in an intensive care unit (ICU). Approximately 21% of the pancreatitis cases occurred within 30 days of starting Januvia or Janumet, and 53% of the cases resolved once the users stopped taking the medication. About half of the cases of pancreatitis with Januvia or Janumet were associated with at least one other risk factor for developing the inflammation of the pancrease, according to the FDA.

In response to the FDA announcement, Merck has said that it does not believe there is any connection between side effects of Januvia and pancreatitis. Januvia generated $462 million in sales worldwide for the pharmaceutical giant in the second quarter of 2009.

Last year, the FDA expressed similar concerns about pancreatitis side effects associated with Byetta, a different medication for treatment of type-2 diabetes. In August 2008, the FDA notified healthcare provides about at least 6 reports of severe necrotizing pancreatitis or hemorrhagic pancreatic among Byetta users, including two deaths.

Following that FDA warning, a number of Byetta lawsuits were filed against the drug’s makers, Amylin Pharmaceuticals and Eli Lilly & Co., on behalf of individuals who developed pancreatitis, alleging that the drug makers have not adequately tested and monitored the side effects of their drug, and failed to adequately warn about the risk of Byetta pancreatitis problems. Amylin and Eli Lilly have also denied that that there is any causal connection between Byetta and pancreatitis.

Two studies were announced earlier this month at a conference of the American Diabetes Association (ADA). One was an independent study done by Medco Health Solutions, Inc., and the other was sponsored by Byetta’s manufacturers, Amylin Pharmaceuticals, Inc. and Eli Lilly & Co. Neither study showed any substantive difference between Byetta (exenatide) and other anti-diabetes therapies in the risk of developing pancreatitis.

The studies comes on the heels of an FDA warning issued in August 2008 that warned healthcare providers about six reports of severe pancreatitis among Byetta users, including two deaths. The drug makers later acknowledged that they were also aware of an additional four pancreatitis deaths linked to their medication.

Byetta is a type 2 diabetes drugs that is used to control blood sugar levels. It is part of a class of medications known as incretin mimetics, which imitate natural hormones that lower blood glucose levels.

The manufacturers’ retrospective cohort study focused on nearly 260,000 patients, using data from health insurance claims databases. The study found that the use of Byetta was “not associated with an increased rate of acute pancreatitis compared to the other antidiabetes medications,” according to a June 7 press release.

The Medco Health study looked at pharmacy and medical claims of 123,621 people with type 2 diabetes who were not using insulin, and found that only .44 percent of Byetta users suffered acute pancreatitis. That compared with .39% of those who used neither drug.

Pancreatitis causes inflammation of the pancreas resulting in symptoms of nausea, vomiting, severe pain in the upper abdomen and back, a rise or fall in blood pressure, increased heart and respiratory rates.

Information about potential pancreatitis side effects of Byetta was added to the drug’s warning label in 2007, after the FDA warned that at least 30 cases of acute pancreatitis had been associated with use of the diabetes drug. Following the 2008 FDA warning, analysts speculated that the FDA was considering a “black box” warning about the potential Byetta pancreatitis risk, which would be the strongest warning that could be placed on a prescription medication.

Amylin and Eli Lilly say they are still investigating the relationship between Byetta and the cases of pancreatitis discovered by the FDA. The Medco Health research is the first study that was not funded by the drug makers that contradicts the prior concerns about pancreatitis and Byetta.