The FDA regularly issues letters to companies that do not follow regulations for manufacturing and marketing. The four letters were issued on separate dates between mid-December and early January.
In a warning letter to Eli Lilly, the FDA said claims appearing a in print ad and the WebMD LLC Little Blue Book regarding Cymbalta do not adequately display information about the drug's side effects. The FDA also said it was not aware of clinical data supporting pain reduction claims made in the ad appearing in the WebMD Little Blue Book. Cymbalta is approved to treat depression, generalized anxiety disorder, diabetic nerve pain and the pain ailment fibromyalgia. Cymbalta's side effects include hepatotoxicity, or liver damage, abnormal bleeding and nausea.
The warning letter for Treanda, which has been associated with side effects including serious infections and skin reactions, said a pocket dosing card for the drug was "false or misleading because it omits important risk information." Cephalon was told to stop disseminating the Treanda dosing card.
The Byetta letter cited statements made by an Eli Lilly representative at the 91st Endocrine Society annual meeting in Washington, D.C. According to the letter, the rep told an FDA official that Byetta had cardiovascular benefits because of a positive effect on cholesterol and triglyceride levels. The agency said it was not aware of any data to support such a claim. The Eli Lilly representative also said Byetta could be used on its own, although the FDA had not yet approved it for independent use. The Byetta letter also said Amylin and Eli Lilly exaggerated the drug's ability to help patients lose weight.
Bayer was cited for a Mirena ad that suggests use of the device increased levels of romance and emotional satisfaction. The FDA said it "not aware of any evidence that suggests that women using Mirena for birth control experience an increase in reconnection, romance or intimacy with their partners." The agency also said that a script it reviewed for a live program on Mirena doesn't adequately convey that if a woman becomes pregnant while on the medicine she may lose her baby.
Byetta was approved in 2005 to help type 2 diabetics on other medications better control blood sugar when other drugs were not adequate. The twice-daily injection is a synthetic form of a lizard hormone that boosts the production of insulin. Insulin is vital to controlling blood sugar levels. Just this past October, Byetta was approved as a stand-alone therapy for type 2 diabetes.
In August 2008, the FDA and Amylin announced six patients taking Byetta had died from pancreatitis. When the FDA approved the expanded use of Byetta, it also announced that the drug's prescribing information would warn about the risk of pancreatitis in patients with severe kidney disease. In November, the agency approved a new label for Byetta amid reports the medicine may cause kidney problems.
The FDA's request for new Byetta safety studies was made public yesterday after a Citigroup analyst said in a note to investors that he had seen the letter the FDA sent Amylin in October approving the expanded used of Byetta. According to Bloomberg.com, when Amylin announced the expanded Byetta approval, it made no mention of the additional studies.
According to a Reuters report, the FDA is requiring the drug maker to conduct the following studies:
*A epidemiological study on acute pancreatitis in Byetta versus non-Byetta patients
*Eidemiologic queries on pancreatic cancer and thyroid neoplasm in Byetta versus patients taking certain alternative therapies
*A clinical trial to see whether Byetta may increase the risk of gall bladder gallstones and therefore pancreatitis
According to Reuters, thyroid neoplasms usually refer to cancer of the thyroid.
According to a statement Amylin released yesterday, some of the studies required by the FDA have already begun. The company maintained that so far, none have shown an increased risk of pancreatitis.
That did little to quell investor concerns however, and Amylin stock fell nearly 10 percent in trading yesterday. According to Bloomberg.com, that is the biggest drop for the stock in eight months of NASDAQ trading.
Byetta was approved by the Food & Drug Administration (FDA) in 2005 to help type 2 diabetics better control blood sugar when other drugs were not adequate. The twice-daily injection is a synthetic form of a lizard hormone that boosts the production of insulin. Insulin is vital to controlling blood sugar levels.
According to a notice posted on the FDA Web site, from April 2005 through October 2008, the agency received 78 cases of altered kidney function (62 cases of acute renal failure and 16 cases of renal insufficiency), in patients using Byetta. Cases of acute renal failure or insufficiency occurred as soon as 3 days and up to 2 years after initiation of Byetta. The patient ages ranged from 23 to 83 years, with an average age of 60 years.
Some cases occurred in patients with pre-existing kidney disease or in patients with one or more risk factors for developing kidney problems, the FDA said. The agency also noted that the most common Byetta side effects include nausea, vomiting, and diarrhea. These side effects may have contributed to the development of altered kidney function. Kidney malfunction can result in a build-up of waste products in the blood, leading to serious illness or life-threatening conditions.
According to the FDA, hospitalization was required in 71 of 78 (91%) patients and there were 4 deaths reported in the cases reviewed. Eighteen patients required dialysis and two patients required kidney transplantation after initiation of Byetta.
Byetta was discontinued in 63 of 78 (80%) patients, with 39 (50%) patients reporting improved signs and symptoms after discontinuation of the drug. One patient experienced recurrent altered kidney function after re-initiation of Byetta.
Due to the serious potential consequences of altered kidney function, the FDA has approved the following revisions to the drug label for Byetta to describe this risk:
* Information regarding post-market reports of acute renal failure and insufficiency, highlighting that Byetta should not be used in patients with severe renal impairment (creatinine clearance <30 ml/min) or end-stage renal disease.
* Recommendations to healthcare professionals that caution should be applied when initiating or increasing doses of Byetta from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 ml/min).
* Recommendations that healthcare professionals monitor patients carefully for the development of kidney dysfunction, and evaluate the continued need for Byetta if kidney dysfunction is suspected while using the product.
* Information about kidney dysfunction in the patient Medication Guide to help patients understand the benefits and potential risks associated with Byetta.
Patients taking Byetta 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, the FDA said. Byetta patients who experience any of these symptoms should immediately discuss them with their health care professional.
Byetta has been the subject of safety concerns for some time. Just last October, the FDA said that 30 people developed pancreatitis that was associated with the use of Byetta. Of those, 5 later suffered from kidney failure. Six patients experienced the onset or worsening of symptoms after their dosage of Byetta was increased from 5 milligrams twice daily to 10 milligrams twice daily. And according to the FDA, pancreatitis symptoms in 22 patients subsided or improved once they quit taking Byetta.
Then on August 18, the FDA said that Byetta had been linked to 6 cases of hemorrhagic or necrotizing pancreatitis in patients taking Byetta since its October alert. All patients required hospitalization, two patients died and four patients were recovering at time of reporting. Byetta was discontinued in all 6 cases. Finally on August 26, Amylin announced that four additional fatalities had been confirmed in Byetta patients suffering from milder forms of pancreatitis.
Amylin and Lilly submitted an application to have Byetta approved as a stand-alone therapy in the first quarter of 2008, Forbes.com said. The companies said the FDA did not request any additional studies. According to Reuters.com, the agency is reviewing several Byetta prescribing information updates submitted by the companies, including revision of safety language.
Another version of Byetta - a long-acting formula - had already been delayed, partly because of the safety concerns surrounding the drug. In a filing with the Securities and Exchange Commission (SEC) last month, Amylin said data submitted for the approval of long-acting Byetta didn’t satisfy the FDA’s standards. In the filing, Amylin said that if the FDA required it to conduct an additional study, it would likely delay its plans to ask for approval by the middle of 2009.
Because of its long-acting nature, once-weekly Byetta cannot be quickly removed from the body, which would be a problem for a patient who developed pancreatitis. In most instances where Byetta patients develop pancreatitis, the problem subsides once treatment is halted. That would not likely be the case with the long-acting version.
Byetta was approved by the FDA in 2005. The twice-daily injection is a synthetic form of a lizard hormone that boosts the production of insulin. Insulin is vital to controlling blood sugar levels.
Byetta, which is jointly marketed by Amylin and Eli Lilly, was approved by the Food & Drug Administration (FDA) in 2005 to help type 2 diabetics better control blood sugar when other drugs were not adequate. The twice-daily injection is a synthetic form of a lizard hormone that boosts the production of insulin. Insulin is vital to controlling blood sugar levels.
Amylin sales have been disappointing all year. Then, on August 18, the FDA said that Byetta had been linked to 6 cases of hemorrhagic or necrotizing pancreatitis in patients taking Byetta since its October alert. All patients required hospitalization, two patients died and four patients were recovering at time of reporting. Byetta was discontinued in all 6 cases. Then, on August 26, Amylin announced that four additional fatalities had been confirmed in Byetta patients suffering from milder forms of pancreatitis.
The problems with Byetta have raised doubts about Amylin's ability to assure approval of a long-acting version of the drug. The new version of Byetta would be taken once-weekly. Because of its long-acting nature, once-weekly Byetta cannot be quickly removed from the body, which would be a problem for a patient who developed pancreatitis. In most instances where Byetta patients develop pancreatitis, the problem subsides once treatment is halted. That would not likely be the case with the long-acting version.
In a filing with the Securities and Exchange Commission (SEC) earlier this month, Amylin revealed that the FDA had rejected data from studies meant to show that new Byetta batches made by partner Alkermes were equivalent to batches made at Amylin’s Ohio facility. If Amylin has to conduct an additional study, it would likely delay its plans to ask for approval by the middle of 2009.
The layoffs announced by Amylin this week involve 340 staffers, and will leave the San Diego company with 1800 employees. Amylin says the move will save $100 million a year.
In a statement, Amylin said it expects Byetta sales to rebound, and the company is currently working with the FDA to update the drug's safety labeling. Amylin is hoping the safety update will not take the form of a black box - the FDA's toughest safety warning - which could further depress sales of Byetta.
The original Byetta was approved by the FDA in 2005 to help type 2 diabetics better control blood sugar when other drugs were not adequate. The twice-daily injection is a synthetic form of a lizard hormone that boosts the production of insulin. Insulin is vital to controlling blood sugar levels. The new version of Byetta would be taken once-weekly.
According to Amylin's filing with the Securities and Exchange Commission (SEC),the FDA rejected data from studies meant to show that new Byetta batches made by partner Alkermes were equivalent to batches made at Amylin's Ohio facility. If Amylin has to conduct an additional study, it would likely delay its plans to ask for approval by the middle of 2009. Amylin said it is continuing discussions with the FDA.
The probable approval delay is just the latest troubling news surrounding Byetta. On August 18, the FDA said that Byetta had been linked to 6 cases of hemorrhagic or necrotizing pancreatitis in patients taking Byetta since its October alert. All patients required hospitalization, two patients died and four patients were recovering at time of reporting. Byetta was discontinued in all 6 cases. Then, on August 26, Amylin announced that four additional fatalities had been confirmed in Byetta patients suffering from milder forms of pancreatitis.
Just last October, the FDA said that 30 people developed pancreatitis that was associated with the use of Byetta. Of those, 5 later suffered from kidney failure. Six patients experienced the onset or worsening of symptoms after their dosage of Byetta was increased from 5 milligrams twice daily to 10 milligrams twice daily. And according to the FDA, pancreatitis symptoms in 22 patients subsided or improved once they quit taking Byetta.
Those safety problems could also ultimately impact the approval prospects for the new version of Byetta. Because of its long-acting nature, once-weekly Byetta cannot be quickly removed from the body, which would be a problem for a patient who developed pancreatitis. In most instances where Byetta patients develop pancreatitis, the problem subsides once treatment is halted. That would not likely be the case with the long-acting version.
Byetta was approved by the Food & Drug Administration (FDA) in 2005 to help type 2 diabetics better control blood sugar when other drugs were not adequate. The twice-daily injection is a synthetic form of a lizard hormone that boosts the production of insulin. Insulin is vital to controlling blood sugar levels.
On August 18, the FDA said that Byetta had been linked to 6 cases of hemorrhagic or necrotizing pancreatitis in patients taking Byetta since its October alert. All patients required hospitalization, two patients died and four patients were recovering at time of reporting. Byetta was discontinued in all 6 cases. Then, on August 26, Amylin announced that four additional fatalities had been confirmed in Byetta patients suffering from milder forms of pancreatitis.
Obviously, the news surrounding Byetta and pancreatitis does not bode well for sales of the drug, which is taken by 700,00 Americans. The side effects reports also have endangered prospects for a once-weekly, long-acting form of Byetta that Amylin had hoped would be approved by 2010. Most drug industry analysts expect that the FDA will now want more information on the new version's side effects before it makes a decision.
The bad Byetta news is taking a toll on Amylin. According to a report on Forbes.com, the company's shares have fallen 44.2% since the pancreatitis news broke in mid-August.
In an attempt to mitigate the damage done to Byetta's reputation, Amylin released a study at European Association for the Study of Diabetes in Rome on Tuesday that compared Byetta with Merck's diabetes treatment Januvia. According to Forbes.com, the study appears to show that Byetta is more potent than Januvia, which is made by Merck & Co.
One analyst told Forbes.com that the study is an attempt by Amylin to salvage its once-promising Byetta. "This is clearly a marketing study to give their reps more stuff to talk about," said Natixis Bleichroeder analyst Jon LeCroy. "You wouldn't do this study unless you knew your drug was better."
Other sources told Forbes that there are also some problems with the study. For one thing, Byetta and Januvia are very different drugs. According to Forbes.com, Januvia is a once-daily pill in the DPP-IV inhibitor class of drugs that is normally prescribed by primary care physicians to patients experiencing the earlier signs of type 2 diabetes. Byetta, a twice daily injectable of the GLP-1 class of drugs, is usually prescribed by a specialist for people with advanced cases of type 2 diabetes that need the added effects of weight loss and appetite suppression.
It also does not appear that Januvia carries the same risk of pancreatitis found with Byetta. According to Forbes.com, in a client note published late last week, Yaron Werber of Citi Investment Research said that of every 100,000 patients who took Byetta, about 6.49 developed acute pancreatitis. The rate of pancreatitis in Januvia patients was only 1.61 out of 100,000, he said. The Forbes report said Werber based this information on the total number of prescriptions written for the drugs.
A much-anticipated long-acting form of Byetta might have problems gaining approval now that the current form of the diabetes drug has been associated with pancreatitis. Amylin Pharmaceuticals had hoped that once-weekly Byetta would be approved by 2010, but now there is a good chance that the Food & Drug Administration (FDA) will want more information on the medication's side effects before it makes a decision.
Byetta was approved by the FDA in 2005 to help type 2 diabetics better control blood sugar when other drugs were not adequate. The twice-daily injection is a synthetic form of a lizard hormone that boosts the production of insulin. Insulin is vital to controlling blood sugar levels.
Last week, the FDA said that Byetta - in its current form - had been linked to 6 cases of hemorrhagic or necrotizing pancreatitis in patients taking Byetta since its October alert. All patients required hospitalization, two patients died and four patients were recovering at time of reporting. Byetta was discontinued in all 6 cases. Late Tuesday, Amylin announced that four additional fatalities had been confirmed in Byetta patients suffering from milder forms of pancreatitis.
Just last October, the FDA said that 30 people developed pancreatitis that was associated with the use of Byetta. Of those, 5 later suffered from kidney failure. Six patients experienced the onset or worsening of symptoms after their dosage of Byetta was increased from 5 milligrams twice daily to 10 milligrams twice daily. And according to the FDA, pancreatitis symptoms in 22 patients subsided or improved once they quit taking Byetta.
Because of its long-acting nature, once-weekly Byetta cannot be quickly removed from the body, which would be a problem for a patient who developed pancreatitis. In most instance where Byetta patients develop pancreatitis, the problem subsides once treatment is halted. That would not likely be the case with the long-acting version.
These concerns could mean that the new form of the drug will face tougher scrutiny from the FDA. One hint of the agency's attitude towards the new version could come when label revisions for current Byetta are made public. The agency wants to "add stronger and more prominent warnings" about the risk of severe pancreatitis to Byetta's label. According to Dow Jones News Service, changes to the label could vary from stronger wording, a change of font or, in the worse-case scenario, a black-box warning. The severity of the change could lead to a tougher review of once-weekly Byetta.
No definite relationship between Byetta and the additional deaths has been proved, Amylin Chief Executive Officer Dan Bradbury said during the call yesterday. All of the deaths involved patients with pancreatitis, but according to a report in "US News and World Report", the FDA did not include the four revealed yesterday in its earlier announcement because they involved a milder form of the disorder.
Last October, the FDA said that 30 people developed pancreatitis that was associated with the use of Byetta. Of those, 5 later suffered from kidney failure. Six patients experienced the onset or worsening of symptoms after their dosage of Byetta was increased from 5 milligrams twice daily to 10 milligrams twice daily. And according to the FDA, pancreatitis symptoms in 22 patients subsided or improved once they quit taking Byetta.
Then last week, the FDA said that it had received reports of 6 cases of hemorrhagic or necrotizing pancreatitis in patients taking Byetta since its October alert. All patients required hospitalization, two patients died and four patients were recovering at time of reporting. Byetta was discontinued in all 6 cases.
Pancreatitis is an inflammation of the pancreas that can cause bleeding, tissue damage and infection. Severe cases of pancreatitis can lead to the release of toxins and enzymes into the blood stream that can injure the heart, lungs, kidneys or other organs. In some instances, acute pancreatitis can be fatal. Hemorrhagic pancreatitis is inflammation that involves bleeding. Necrotizing pancreatitis occurs when the inflamed pancreas destroys itself.
The FDA said last week it was working with Eli Lilly and Amylin to add stronger and more prominent warnings to Byetta's label. That could include upgrading a current precaution on pancreatitis to a warning, or changing the wording.
Byetta was approved by the FDA in 2005 to help type 2 diabetics better control blood sugar when other drugs were not adequate. The twice-daily injection is a synthetic form of a lizard hormone that boosts the production of insulin. Insulin is vital to controlling blood sugar levels.
Byetta is made by Amylin Pharmaceuticals Inc. The drug was approved by the FDA in 2005 to help type 2 diabetics better control blood sugar when other drugs were not adequate. The twice-daily injection is a synthetic form of a lizard hormone that boosts the production of insulin. Insulin is vital to controlling blood sugar levels.
Pancreatitis is an inflammation of the pancreas that can cause bleeding, tissue damage and infection. Severe cases of pancreatitis can lead to the release of toxins and enzymes into the blood stream that can injure the heart, lungs, kidneys or other organs. In some instances, acute pancreatitis can be fatal.
Last October, the FDA said that 30 people developed pancreatitis that was associated with the use of Byetta. Of those, 5 later suffered from kidney failure. Six patients experienced the onset or worsening of symptoms after their dosage of Byetta was increased from 5 milligrams twice daily to 10 milligrams twice daily. And according to the FDA, pancreatitis symptoms in 22 patients subsided or improved once they quit taking Byetta.
At that time, the FDA said that Amylin had agreed to include information about acute pancreatitis in the PRECAUTIONS section of the Byetta label, but that information has yet to be added.
Today, the FDA said that it had received reports of 6 cases of hemorrhagic or necrotizing pancreatitis in patients taking Byetta since its October alert. All patients required hospitalization, two patients died and four patients were recovering at time of reporting. Byetta was discontinued in all 6 cases.
The FDA alert said that Byetta and other potentially suspect drugs should be promptly discontinued if pancreatitis is suspected. There are no signs or symptoms that distinguish acute hemorrhagic or necrotizing pancreatitis associated with Byetta from the less severe form of pancreatitis. If pancreatitis is confirmed, doctors should initiate appropriate treatment and carefully monitor the patient until recovery. Byetta should not be restarted. Doctors should consider antidiabetic therapies other than Byetta in patients with a history of pancreatitis, the FDA said.
The FDA also said that healthcare professionals should instruct patients taking Byetta to seek prompt medical care if they experience unexplained persistent severe abdominal pain which may or may not be accompanied by vomiting.
The FDA said it is working with Amylin to add stronger and more prominent warnings in the product label about the risk of acute hemorrhagic or necrotizing pancreatitis.
Pancreatitis is an inflammation of the pancreas that can cause bleeding, tissue damage and infection. Severe cases of pancreatitis can lead to the release of toxins and enzymes into the blood stream that can injure the heart, lungs, kidneys or other organs. In some instances, acute pancreatitis can be fatal According to the FDA, 30 people have developed pancreatitis that has been associated with the use of Byetta. Of those, 5 later suffered from kidney failure. Six patients experienced the onset or worsening of symptoms after their dosage of Byetta was increased from 5 milligrams twice daily to 10 milligrams twice daily. And according to the FDA, pancreatitis symptoms in 22 patients subsided or improved once they quit taking Byetta.
Byetta is marketed jointly by Amylin Pharmaceuticals Inc. and Eli Lilly & Co. The drug was approved by the FDA in 2005 to help type 2 diabetics better control blood sugar when other drugs were not adequate. The twice-daily injection is a synthetic form of a lizard hormone that boosts the production of insulin. Insulin is vital to controlling blood sugar levels.
The changes to the Byetta side effects warnings will say that the drug has been associated with the development of pancreatitis. The FDA is also urging physicians and patients to be alert to warning signs for the disorder, including persistent and severe abdominal pain that can radiate to the back. The pain can be accompanied by nausea and vomiting. Some of these symptoms are themselves common side effects of Byetta, but the FDA said that the symptoms of pancreatitis would be much more severe and persistent. The FDA said that patients who develop pancreatitis should stop taking Byetta immediately.
Amylin and Eli Lilly agreed to update the Byetta side effects labeling at the FDA’s request. According to the companies, information about pancreatitis had already been included on the Byetta label. But the new Byetta side effects information will be more detailed and will give clear advice on what signs and symptoms doctors and patients need to be aware of.
Byetta is one of the fastest growing diabetes drugs on the market, and has been used by about 700,000 patients in the US since it was first introduced.