Elizabeth Mechcatie

Companies that manufacture, distribute, and/or market unapproved formulations of the oral, single ingredient forms of the gout drug colchicine have been ordered to stop doing so, the Food and Drug Administration announced on Sept. 30.

The companies must stop manufacturing these products within 45 days of the announcement and stop shipping unapproved colchicine within 90 days of the announcement, according to the statement, which says that a small amount of unapproved colchicine will be available after these dates, until supplies are used up.

Oral colchicine products are among the drugs that have been on the market for so many years that they were never subjected to the current prescription drug approval process. The FDA has launched an initiative to target the manufacturers of colchicine and other older, unapproved drugs to conduct the necessary testing to meet current approval standards or take them off the market.

Once the older products are off the market, the only oral colchicine product that will be available is Colcrys, marketed by Mutual Pharmaceuticals/URL Pharma, which was approved in 2009, after the company met the current drug approval requirements. As a result, the drug’s label includes information on safety data, drug interactions, and dosing that is not available for the older unapproved versions, according to the FDA.

The FDA's approval of Colcrys and the plans to ban the marketing of the older products has been sharply criticized by some clinicians who treat patients with gout because Colcrys is significantly more expensive than the older, unapproved formulations.

The FDA statement notes that the manufacturer of Colcrys has established a patient assistance program for patients who can’t afford the brand-name drug and those on Medicare who don’t want the cost of the drug to contribute to their out-of-pocket Medicare Part D expenses. More information about that program is available at the Colcrys Web site or at Needy Meds, an umbrella organization that offers patient assistance, or by calling 888-811-8423. The company has said that the program will continue "at a minimum until there is FDA-approved generic competition" for Colcrys, according to the statement.

The agency is encouraging manufacturers of such products to pursue approval of their products or "to face the type of action announced today," Deborah Autor, director of the office of compliance at the FDA's Center for Drug Evaluation and Research (CDER), said in the statement.

The FDA ordered a halt to unapproved colchicine for injection products in 2008.

Companies that manufacture, distribute, and/or market unapproved formulations of the oral, single ingredient forms of the gout drug colchicine have been ordered to stop doing so, the Food and Drug Administration announced on Sept. 30.

The companies must stop manufacturing these products within 45 days of the announcement and stop shipping unapproved colchicine within 90 days of the announcement, according to the statement, which says that a small amount of unapproved colchicine will be available after these dates, until supplies are used up.

Oral colchicine products are among the drugs that have been on the market for so many years that they were never subjected to the current prescription drug approval process. The FDA has launched an initiative to target the manufacturers of colchicine and other older, unapproved drugs to conduct the necessary testing to meet current approval standards or take them off the market.

Once the older products are off the market, the only oral colchicine product that will be available is Colcrys, marketed by Mutual Pharmaceuticals/URL Pharma, which was approved in 2009, after the company met the current drug approval requirements. As a result, the drug’s label includes information on safety data, drug interactions, and dosing that is not available for the older unapproved versions, according to the FDA.

The FDA's approval of Colcrys and the plans to ban the marketing of the older products has been sharply criticized by some clinicians who treat patients with gout because Colcrys is significantly more expensive than the older, unapproved formulations.

The FDA statement notes that the manufacturer of Colcrys has established a patient assistance program for patients who can’t afford the brand-name drug and those on Medicare who don’t want the cost of the drug to contribute to their out-of-pocket Medicare Part D expenses. More information about that program is available at the Colcrys Web site or at Needy Meds, an umbrella organization that offers patient assistance, or by calling 888-811-8423. The company has said that the program will continue "at a minimum until there is FDA-approved generic competition" for Colcrys, according to the statement.

The agency is encouraging manufacturers of such products to pursue approval of their products or "to face the type of action announced today," Deborah Autor, director of the office of compliance at the FDA's Center for Drug Evaluation and Research (CDER), said in the statement.

The FDA ordered a halt to unapproved colchicine for injection products in 2008.

Companies that manufacture, distribute, and/or market unapproved formulations of the oral, single ingredient forms of the gout drug colchicine have been ordered to stop doing so, the Food and Drug Administration announced on Sept. 30.

The companies must stop manufacturing these products within 45 days of the announcement and stop shipping unapproved colchicine within 90 days of the announcement, according to the statement, which says that a small amount of unapproved colchicine will be available after these dates, until supplies are used up.

Oral colchicine products are among the drugs that have been on the market for so many years that they were never subjected to the current prescription drug approval process. The FDA has launched an initiative to target the manufacturers of colchicine and other older, unapproved drugs to conduct the necessary testing to meet current approval standards or take them off the market.

Once the older products are off the market, the only oral colchicine product that will be available is Colcrys, marketed by Mutual Pharmaceuticals/URL Pharma, which was approved in 2009, after the company met the current drug approval requirements. As a result, the drug’s label includes information on safety data, drug interactions, and dosing that is not available for the older unapproved versions, according to the FDA.

The FDA's approval of Colcrys and the plans to ban the marketing of the older products has been sharply criticized by some clinicians who treat patients with gout because Colcrys is significantly more expensive than the older, unapproved formulations.

The FDA statement notes that the manufacturer of Colcrys has established a patient assistance program for patients who can’t afford the brand-name drug and those on Medicare who don’t want the cost of the drug to contribute to their out-of-pocket Medicare Part D expenses. More information about that program is available at the Colcrys Web site or at Needy Meds, an umbrella organization that offers patient assistance, or by calling 888-811-8423. The company has said that the program will continue "at a minimum until there is FDA-approved generic competition" for Colcrys, according to the statement.

The agency is encouraging manufacturers of such products to pursue approval of their products or "to face the type of action announced today," Deborah Autor, director of the office of compliance at the FDA's Center for Drug Evaluation and Research (CDER), said in the statement.

The FDA ordered a halt to unapproved colchicine for injection products in 2008.

Cognition and neuroanatomy differed between carriers and non-carriers of the e4 allele of the apolipoprotein E gene in a study that compared the phenotypic expression of the allele in people with mild Alzheimer's disease.

“We found the presence or absence of the APOE e4 allele influences the cognitive and anatomic phenotypic expression of AD in a dissociable manner,” concluded Dr. David A. Wolk of the University of Pennsylvania, Philadelphia, and his coauthors in the Alzheimer's Disease Neuroimaging Initiative.

The results “have important implications for the early detection and monitoring of AD, because APOE carrier status seems to exert a strong influence on the cognitive and anatomic expression of the disease” (Proc. Natl. Acad. Sci. U.S.A. 2010 May 17 [doi: 10.1073/pnas.1001412107]).

The e4 allele is “the major genetic risk factor” for AD and is one of the three major alleles of the APOE gene, which codes for a lipid transport protein. Previously available data on the association between APOE allele carrier status and phenotypic differences have varied or have been inconsistent, according to the investigators.

To address concerns over possible misdiagnoses, Dr. Wolk included cerebrospinal fluid testing data to improve the accuracy of the diagnosis of Alzheimer's disease in the study's 67 e4 carriers and 24 noncarriers.

The APOE e4 carriers had significantly greater impairments in delayed recall as well as recognition memory and memory retention. In comparison, non-carriers showed significantly greater impairments in tests of working memory, executive control, and lexical access.

In a statement from the university, Dr. Wolk's co-author, Dr. Bradford Dickerson of Massachusetts General Hospital, Boston, referred to recent studies describing differences in the way in which Alzheimer's patients responded to drugs, based on whether they had the APOE e4 allele or not. “Rather than restricting trials exclusively to patients with or without APOE e4, the results suggest that different behavioral and brain measures might be a useful approach to consider in evaluating investigational drugs,” he said.

Disclosures: The authors had no conflicts of interest to disclose. The study was primarily funded by the ADNI, which is funded by the National Institute of Aging and the National Institute of Biomedical Imaging and Bioengineering, and the Foundation for the National Institutes of Health, through contributions from several pharmaceutical companies.

Cognition and neuroanatomy differed between carriers and non-carriers of the e4 allele of the apolipoprotein E gene in a study that compared the phenotypic expression of the allele in people with mild Alzheimer's disease.

“We found the presence or absence of the APOE e4 allele influences the cognitive and anatomic phenotypic expression of AD in a dissociable manner,” concluded Dr. David A. Wolk of the University of Pennsylvania, Philadelphia, and his coauthors in the Alzheimer's Disease Neuroimaging Initiative.

The results “have important implications for the early detection and monitoring of AD, because APOE carrier status seems to exert a strong influence on the cognitive and anatomic expression of the disease” (Proc. Natl. Acad. Sci. U.S.A. 2010 May 17 [doi: 10.1073/pnas.1001412107]).

The e4 allele is “the major genetic risk factor” for AD and is one of the three major alleles of the APOE gene, which codes for a lipid transport protein. Previously available data on the association between APOE allele carrier status and phenotypic differences have varied or have been inconsistent, according to the investigators.

To address concerns over possible misdiagnoses, Dr. Wolk included cerebrospinal fluid testing data to improve the accuracy of the diagnosis of Alzheimer's disease in the study's 67 e4 carriers and 24 noncarriers.

The APOE e4 carriers had significantly greater impairments in delayed recall as well as recognition memory and memory retention. In comparison, non-carriers showed significantly greater impairments in tests of working memory, executive control, and lexical access.

In a statement from the university, Dr. Wolk's co-author, Dr. Bradford Dickerson of Massachusetts General Hospital, Boston, referred to recent studies describing differences in the way in which Alzheimer's patients responded to drugs, based on whether they had the APOE e4 allele or not. “Rather than restricting trials exclusively to patients with or without APOE e4, the results suggest that different behavioral and brain measures might be a useful approach to consider in evaluating investigational drugs,” he said.

Disclosures: The authors had no conflicts of interest to disclose. The study was primarily funded by the ADNI, which is funded by the National Institute of Aging and the National Institute of Biomedical Imaging and Bioengineering, and the Foundation for the National Institutes of Health, through contributions from several pharmaceutical companies.

Cognition and neuroanatomy differed between carriers and non-carriers of the e4 allele of the apolipoprotein E gene in a study that compared the phenotypic expression of the allele in people with mild Alzheimer's disease.

“We found the presence or absence of the APOE e4 allele influences the cognitive and anatomic phenotypic expression of AD in a dissociable manner,” concluded Dr. David A. Wolk of the University of Pennsylvania, Philadelphia, and his coauthors in the Alzheimer's Disease Neuroimaging Initiative.

The results “have important implications for the early detection and monitoring of AD, because APOE carrier status seems to exert a strong influence on the cognitive and anatomic expression of the disease” (Proc. Natl. Acad. Sci. U.S.A. 2010 May 17 [doi: 10.1073/pnas.1001412107]).

The e4 allele is “the major genetic risk factor” for AD and is one of the three major alleles of the APOE gene, which codes for a lipid transport protein. Previously available data on the association between APOE allele carrier status and phenotypic differences have varied or have been inconsistent, according to the investigators.

To address concerns over possible misdiagnoses, Dr. Wolk included cerebrospinal fluid testing data to improve the accuracy of the diagnosis of Alzheimer's disease in the study's 67 e4 carriers and 24 noncarriers.

The APOE e4 carriers had significantly greater impairments in delayed recall as well as recognition memory and memory retention. In comparison, non-carriers showed significantly greater impairments in tests of working memory, executive control, and lexical access.

In a statement from the university, Dr. Wolk's co-author, Dr. Bradford Dickerson of Massachusetts General Hospital, Boston, referred to recent studies describing differences in the way in which Alzheimer's patients responded to drugs, based on whether they had the APOE e4 allele or not. “Rather than restricting trials exclusively to patients with or without APOE e4, the results suggest that different behavioral and brain measures might be a useful approach to consider in evaluating investigational drugs,” he said.

Disclosures: The authors had no conflicts of interest to disclose. The study was primarily funded by the ADNI, which is funded by the National Institute of Aging and the National Institute of Biomedical Imaging and Bioengineering, and the Foundation for the National Institutes of Health, through contributions from several pharmaceutical companies.

Companies that manufacture, distribute, and/or market unapproved formulations of the oral, single ingredient forms of the gout drug colchicine have been ordered to stop doing so, the Food and Drug Administration announced on Sept. 30.

The companies must stop manufacturing these products within 45 days of the announcement and stop shipping unapproved colchicine within 90 days of the announcement, according to the statement, which says that a small amount of unapproved colchicine will be available after these dates, until supplies are used up.

Oral colchicine products are among the drugs that have been on the market for so many years that they were never subjected to the current prescription drug approval process. The FDA has launched an initiative to target the manufacturers of colchicine and other older, unapproved drugs to conduct the necessary testing to meet current approval standards or take them off the market.

Once the older products are off the market, the only oral colchicine product that will be available is Colcrys, marketed by Mutual Pharmaceuticals/URL Pharma, which was approved in 2009, after the company met the current drug approval requirements. As a result, the drug’s label includes information on safety data, drug interactions, and dosing that is not available for the older unapproved versions, according to the FDA.

The FDA’s approval of Colcrys and the plans to ban the marketing of the older products has been sharply criticized by some clinicians who treat patients with gout because Colcrys is significantly more expensive than the older, unapproved formulations.

The FDA statement notes that the manufacturer of Colcrys has established a patient assistance program for patients who can’t afford the brand-name drug and those on Medicare who don’t want the cost of the drug to contribute to their out-of-pocket Medicare Part D expenses. More information about that program is available at the Colcrys Web site or at Needy Meds, an umbrella organization that offers patient assistance, or by calling 888-811-8423. The company has said that the program will continue “at a minimum until there is FDA-approved generic competition” for Colcrys, according to the statement.

The agency is encouraging manufacturers of such products to pursue approval of their products or “to face the type of action announced today,” Deborah Autor, director of the office of compliance at the FDA’s Center for Drug Evaluation and Research (CDER), said in the statement.

The FDA ordered a halt to unapproved colchicine for injection products in 2008.

Companies that manufacture, distribute, and/or market unapproved formulations of the oral, single ingredient forms of the gout drug colchicine have been ordered to stop doing so, the Food and Drug Administration announced on Sept. 30.

The companies must stop manufacturing these products within 45 days of the announcement and stop shipping unapproved colchicine within 90 days of the announcement, according to the statement, which says that a small amount of unapproved colchicine will be available after these dates, until supplies are used up.

Oral colchicine products are among the drugs that have been on the market for so many years that they were never subjected to the current prescription drug approval process. The FDA has launched an initiative to target the manufacturers of colchicine and other older, unapproved drugs to conduct the necessary testing to meet current approval standards or take them off the market.

Once the older products are off the market, the only oral colchicine product that will be available is Colcrys, marketed by Mutual Pharmaceuticals/URL Pharma, which was approved in 2009, after the company met the current drug approval requirements. As a result, the drug’s label includes information on safety data, drug interactions, and dosing that is not available for the older unapproved versions, according to the FDA.

The FDA’s approval of Colcrys and the plans to ban the marketing of the older products has been sharply criticized by some clinicians who treat patients with gout because Colcrys is significantly more expensive than the older, unapproved formulations.

The FDA statement notes that the manufacturer of Colcrys has established a patient assistance program for patients who can’t afford the brand-name drug and those on Medicare who don’t want the cost of the drug to contribute to their out-of-pocket Medicare Part D expenses. More information about that program is available at the Colcrys Web site or at Needy Meds, an umbrella organization that offers patient assistance, or by calling 888-811-8423. The company has said that the program will continue “at a minimum until there is FDA-approved generic competition” for Colcrys, according to the statement.

The agency is encouraging manufacturers of such products to pursue approval of their products or “to face the type of action announced today,” Deborah Autor, director of the office of compliance at the FDA’s Center for Drug Evaluation and Research (CDER), said in the statement.

The FDA ordered a halt to unapproved colchicine for injection products in 2008.

Companies that manufacture, distribute, and/or market unapproved formulations of the oral, single ingredient forms of the gout drug colchicine have been ordered to stop doing so, the Food and Drug Administration announced on Sept. 30.

The companies must stop manufacturing these products within 45 days of the announcement and stop shipping unapproved colchicine within 90 days of the announcement, according to the statement, which says that a small amount of unapproved colchicine will be available after these dates, until supplies are used up.

Oral colchicine products are among the drugs that have been on the market for so many years that they were never subjected to the current prescription drug approval process. The FDA has launched an initiative to target the manufacturers of colchicine and other older, unapproved drugs to conduct the necessary testing to meet current approval standards or take them off the market.

Once the older products are off the market, the only oral colchicine product that will be available is Colcrys, marketed by Mutual Pharmaceuticals/URL Pharma, which was approved in 2009, after the company met the current drug approval requirements. As a result, the drug’s label includes information on safety data, drug interactions, and dosing that is not available for the older unapproved versions, according to the FDA.

The FDA’s approval of Colcrys and the plans to ban the marketing of the older products has been sharply criticized by some clinicians who treat patients with gout because Colcrys is significantly more expensive than the older, unapproved formulations.

The FDA statement notes that the manufacturer of Colcrys has established a patient assistance program for patients who can’t afford the brand-name drug and those on Medicare who don’t want the cost of the drug to contribute to their out-of-pocket Medicare Part D expenses. More information about that program is available at the Colcrys Web site or at Needy Meds, an umbrella organization that offers patient assistance, or by calling 888-811-8423. The company has said that the program will continue “at a minimum until there is FDA-approved generic competition” for Colcrys, according to the statement.

The agency is encouraging manufacturers of such products to pursue approval of their products or “to face the type of action announced today,” Deborah Autor, director of the office of compliance at the FDA’s Center for Drug Evaluation and Research (CDER), said in the statement.

The FDA ordered a halt to unapproved colchicine for injection products in 2008.

Although the Food and Drug Administration’s decision to keep rosiglitazone on the market with a risk management program in place that preserves some access to the controversial diabetes drug, the plan is expected to squelch most prescribing and therefore, could have an effect that approaches that in Europe, where it will no longer be marketed.

Under a risk evaluation and mitigation strategy (REMS), rosiglitazone will be available only to new patients with type 2 diabetes who are unable to adequately manage their blood glucose on pioglitazone or are unable to take pioglitazone, the only other approved thiazolidinedione (TZD). However, patients who are already taking rosiglitazone may continue if, through the REMS program, they acknowledge their understanding of the drug’s potential cardiac risks, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said during a press briefing this week. About 600,000 U.S. patients are taking the drug; Dr. Woodcock said the REMS program will “significantly reduce” that number, while ensuring that those who continue will fully understand its potential risk.

Additionally, the FDA instructed the drug’s manufacturer, GlaxoSmithKline, to commission an independent readjudication of the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes) trial, which was submitted to the FDA in August 2009 and was undertaken to further explore cardiovascular safety signals seen in earlier trials.

At the same time, the European Medicines Agency announced it was pulling it off the shelves in the European Union, based on the same evidence reviewed by the FDA.

The FDA’s decision reflects the majority opinion of an FDA advisory panel, which in July met to review the cardiovascular safety data of the drug. The majority of the panel members voted to keep the drug on the market but with more warnings and restrictions on its use, but a significant proportion advocated that it should be taken off the market.

Rosiglitazone has been dogged for years by conflicting data on its cardiovascular safety profile and the decision to restrict access came on the heels of an ever-increasing debate about rosiglitazone’s cardiovascular safety. The RECORD trial, sponsored by GlaxoSmithKline, found no increased risk in myocardial infarction, overall death, or cardiovascular death. But several trials came to conflicting conclusions about whether the drug increased the risk of MI; a highly touted 2007 meta-analysis of 42 studies concluded that it increased that risk by up to 43%, and the risk of cardiovascular death by up to 64% (N. Engl. J. Med. 2007;356:2457-71).

The lead author of the meta-analysis, Dr. Steven E. Nissen, a vocal advocate for the withdrawal of rosiglitazone from the market, said in an interview that both the FDA and EMA decisions will result in almost the same outcomes and that rosiglitazone will soon be rarely used.

Even though the FDA did not opt for market withdrawal, the drug in the United States “is essentially off the market,” as long as the REMS is well executed, which he expects it will be. “What you have to actually do in order to prescribe the drug now is you have to say you’ve tried every other diabetes drug, including pioglitazone, and the patient couldn’t tolerate them. There’s nobody that meets that description,” said Dr. Nissen, chairman of the department of cardiovascular medicine, Cleveland Clinic Foundation.

At the July panel meeting, Dr. Nissen told the panel and the FDA that, with another thiazolidinedione available as an alternative (pioglitazone), continued marketing of rosiglitazone could not be medically or ethically justified. But, in the interview, he was positive about the agency’s decision. His message to clinicians is to “stop using the drug, get people on something else, and move on.”

Endocrinologist Clifford Rosen agreed. “This effectively puts an end to rosiglitazone in the United States ... it will be very, very rare to have a patient on rosiglitazone,” said Dr. Rosen, professor of medicine at Tufts University, Boston, and senior scientist at Maine Medical Center, Scarborough. He was among the 10 panel members at the July meeting who voted in favor of allowing continued marketing but with more warnings in the label and restrictions in its use.

The FDA decision “basically puts an end to rosiglitazone prescriptions in the United States,” he said in an interview. “It’s almost impossible for an individual practitioner to write a prescription after spending 20 minutes talking about risk, having the patient sign an informed consent and then filling out forms to send to the FDA. It’s just not going to happen.”

Dr. Rosen added that he expects that most patients who are on the drug now will probably be switched to other drugs. “Maybe a few people who have been on it for a long time, feel great, and have good glucose control might stay on it, but those individuals still need to have full informed consent and have the risks explained to them.”

Keeping a patient on rosiglitazone under the REMS “will be an onerous task” and the use of the drug will be “minimal,” said Dr. Paul Jellinger, professor of clinical medicine, University of Miami, and past president of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Patients can easily be switched form rosiglitazone to pioglitazone, or a non-TZD drug, such as an incretin-based treatment, he said in an interview.

Dr. Jellinger said that he thought the FDA decision was appropriate and that the FDA acted on behalf of patient safety, based on substantial amount of data. Although there was “considerable uncertainty, there remains a potential risk and there is a signal that suggests there may be a relationship.”

One of the cardiologists on the panel in July, Dr. Sanjay Kaul of the Cedars-Sinai Heart Institute in Los Angeles, said in an interview that the FDA’s decision is “the right call to keep the drug accessible but with significant restrictions that have teeth.” The decision, though, “reflects the uncertainty in the evidence – it is insufficient to either implicate the drug or exonerate it.”

During the press briefing, Dr. Woodcock said, “We still believe there is considerable uncertainty about the magnitude of the cardiovascular risk.” RECORD was an open-label trial, “and it was determined that we can’t rely on those results, even though they did not show a significantly increased risk of cardiac harm. Therefore, the questions raised by the meta-analysis have not really been answered,” she said.

The FDA also decided to terminate the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, also sponsored by GlaxoSmithKline, which was designed to determine any difference in cardiovascular safety between rosiglitazone and pioglitazone. In July, the FDA put TIDE on a partial hold, allowing patient enrollment but not treatment. The panel had voted 19-11 to continue the TIDE trial, if rosiglitazone remained on the U.S. market.

Dr. Rosen, who was among those strongly opposed to continuing the study, lauded the decision to halt the TIDE study because it would be unethical to continue the study and subject people to a randomized trial that involved a drug ”where we know the risk and benefit is not established beyond pioglitazone.”

Dr. Kaul was among the panelists who supported continuing TIDE. ”If you stop the study, how else are you going to resolve this uncertainty,” he said. But he agrees with the FDA decision. “The FDA had to do what they did,” but pointed out that considerable controversy over the drug remains.

Dr. Jellinger also would have liked the TIDE study to continue, and found it “unusual” that the gold standard of clinical trials, the prospective randomized, controlled study, was trumped by studies like meta-analyses.

During the press briefing, Dr. Woodcock said that the signal of increased risk “has not been completely refuted by any evidence, so we think it is prudent to restrict access and make sure that those using and prescribing the medication are aware of the facts and make the choice in an informed manner.”

It will take several months to fully implement the REMS program, Dr. Joshua Sharfstein said during the briefing. Until then, “Patients who are taking rosiglitazone should continue to do so, and consult their physician to discuss the possibility of selecting another medication without this concern of cardiac ischemia,” said Dr. Sharfstein, FDA’s principal deputy commissioner. “Once the REMS is in place, physicians will need to enroll patients before they can continue to receive the drug.”

When the REMS is active, Dr. Sharfstein reiterated, rosiglitazone will be available only to patients who cannot control their blood sugar on any other medication and who are unable to take pioglitazone for medical reasons. “Doctors will have to document this, and also that they have discussed the risks of rosiglitazone in order for the patient to receive the drug.”

Researchers had hoped the RECORD study would set the rosiglitazone risk story straight. But in July, the FDA panel tasked with reviewing the drug’s safety questioned RECORD and its adjudication of cardiovascular events. The independent review of RECORD’s adjudication at a patient record level will be done, Dr. Sharfstein said, “to catch events that occurred but which might have not been properly referred to the adjudication committee.”

In a press statement, Dr. Ellen Strahlman, GlaxoSmithKline’s chief medical officer, said, “Our primary concern continues to be patients with type 2 diabetes, and we are making every effort to ensure that physicians in Europe and the U.S. have all the information they need to help them understand how these regulatory decisions affect them and their patients.”

The statement noted that “the company continues to believe that [rosiglitazone] is an important treatment for patients with type 2 diabetes and is now working with the FDA and EMA to implement the required actions ... GSK will voluntarily cease promotion of [rosiglitazone] in all the countries in which it operates and will continue to respond to requests for information and support from healthcare professionals and patients.”

But other REMS programs – including the one that will be established for rosiglitazone – are much more restrictive, such as the one for the antiepileptic vigabatrin. That REMS requires not only a medication guide, but also a communication plan to ensure reporting of adverse events, elements to assure safe use, and a system to ensure that physicians, pharmacies, and patients who do not comply with the rules lose access to the drug.

Dr. Nissen has received research support from Takeda Pharmaceutical Co., AstraZeneca, Daiichi Sankyo Co., and several other pharmaceutical companies and has consulted for a many such companies without financial compensation. All payments from any for-profit entity are paid directly to charity. Dr. Rosen reports receiving a lecture fee from GlaxoSmithKline and grant support from Eli Lilly & Co., Merck & Co., and Novartis. Dr. Kaul has received research support from Hoffmann-La Roche and has been a consultant for that company as well as from Novo-Nordisk. Dr. Jellinger is on the speakers bureaus of Amylin Pharmaceuticals, Eli Lilly, Merck, Novo-Nordisk, Sanofi-Aventis, and Takeda.

Although the Food and Drug Administration’s decision to keep rosiglitazone on the market with a risk management program in place that preserves some access to the controversial diabetes drug, the plan is expected to squelch most prescribing and therefore, could have an effect that approaches that in Europe, where it will no longer be marketed.

Under a risk evaluation and mitigation strategy (REMS), rosiglitazone will be available only to new patients with type 2 diabetes who are unable to adequately manage their blood glucose on pioglitazone or are unable to take pioglitazone, the only other approved thiazolidinedione (TZD). However, patients who are already taking rosiglitazone may continue if, through the REMS program, they acknowledge their understanding of the drug’s potential cardiac risks, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said during a press briefing this week. About 600,000 U.S. patients are taking the drug; Dr. Woodcock said the REMS program will “significantly reduce” that number, while ensuring that those who continue will fully understand its potential risk.

Additionally, the FDA instructed the drug’s manufacturer, GlaxoSmithKline, to commission an independent readjudication of the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes) trial, which was submitted to the FDA in August 2009 and was undertaken to further explore cardiovascular safety signals seen in earlier trials.

At the same time, the European Medicines Agency announced it was pulling it off the shelves in the European Union, based on the same evidence reviewed by the FDA.

The FDA’s decision reflects the majority opinion of an FDA advisory panel, which in July met to review the cardiovascular safety data of the drug. The majority of the panel members voted to keep the drug on the market but with more warnings and restrictions on its use, but a significant proportion advocated that it should be taken off the market.

Rosiglitazone has been dogged for years by conflicting data on its cardiovascular safety profile and the decision to restrict access came on the heels of an ever-increasing debate about rosiglitazone’s cardiovascular safety. The RECORD trial, sponsored by GlaxoSmithKline, found no increased risk in myocardial infarction, overall death, or cardiovascular death. But several trials came to conflicting conclusions about whether the drug increased the risk of MI; a highly touted 2007 meta-analysis of 42 studies concluded that it increased that risk by up to 43%, and the risk of cardiovascular death by up to 64% (N. Engl. J. Med. 2007;356:2457-71).

The lead author of the meta-analysis, Dr. Steven E. Nissen, a vocal advocate for the withdrawal of rosiglitazone from the market, said in an interview that both the FDA and EMA decisions will result in almost the same outcomes and that rosiglitazone will soon be rarely used.

Even though the FDA did not opt for market withdrawal, the drug in the United States “is essentially off the market,” as long as the REMS is well executed, which he expects it will be. “What you have to actually do in order to prescribe the drug now is you have to say you’ve tried every other diabetes drug, including pioglitazone, and the patient couldn’t tolerate them. There’s nobody that meets that description,” said Dr. Nissen, chairman of the department of cardiovascular medicine, Cleveland Clinic Foundation.

At the July panel meeting, Dr. Nissen told the panel and the FDA that, with another thiazolidinedione available as an alternative (pioglitazone), continued marketing of rosiglitazone could not be medically or ethically justified. But, in the interview, he was positive about the agency’s decision. His message to clinicians is to “stop using the drug, get people on something else, and move on.”

Endocrinologist Clifford Rosen agreed. “This effectively puts an end to rosiglitazone in the United States ... it will be very, very rare to have a patient on rosiglitazone,” said Dr. Rosen, professor of medicine at Tufts University, Boston, and senior scientist at Maine Medical Center, Scarborough. He was among the 10 panel members at the July meeting who voted in favor of allowing continued marketing but with more warnings in the label and restrictions in its use.

The FDA decision “basically puts an end to rosiglitazone prescriptions in the United States,” he said in an interview. “It’s almost impossible for an individual practitioner to write a prescription after spending 20 minutes talking about risk, having the patient sign an informed consent and then filling out forms to send to the FDA. It’s just not going to happen.”

Dr. Rosen added that he expects that most patients who are on the drug now will probably be switched to other drugs. “Maybe a few people who have been on it for a long time, feel great, and have good glucose control might stay on it, but those individuals still need to have full informed consent and have the risks explained to them.”

Keeping a patient on rosiglitazone under the REMS “will be an onerous task” and the use of the drug will be “minimal,” said Dr. Paul Jellinger, professor of clinical medicine, University of Miami, and past president of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Patients can easily be switched form rosiglitazone to pioglitazone, or a non-TZD drug, such as an incretin-based treatment, he said in an interview.

Dr. Jellinger said that he thought the FDA decision was appropriate and that the FDA acted on behalf of patient safety, based on substantial amount of data. Although there was “considerable uncertainty, there remains a potential risk and there is a signal that suggests there may be a relationship.”

One of the cardiologists on the panel in July, Dr. Sanjay Kaul of the Cedars-Sinai Heart Institute in Los Angeles, said in an interview that the FDA’s decision is “the right call to keep the drug accessible but with significant restrictions that have teeth.” The decision, though, “reflects the uncertainty in the evidence – it is insufficient to either implicate the drug or exonerate it.”

During the press briefing, Dr. Woodcock said, “We still believe there is considerable uncertainty about the magnitude of the cardiovascular risk.” RECORD was an open-label trial, “and it was determined that we can’t rely on those results, even though they did not show a significantly increased risk of cardiac harm. Therefore, the questions raised by the meta-analysis have not really been answered,” she said.

The FDA also decided to terminate the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, also sponsored by GlaxoSmithKline, which was designed to determine any difference in cardiovascular safety between rosiglitazone and pioglitazone. In July, the FDA put TIDE on a partial hold, allowing patient enrollment but not treatment. The panel had voted 19-11 to continue the TIDE trial, if rosiglitazone remained on the U.S. market.

Dr. Rosen, who was among those strongly opposed to continuing the study, lauded the decision to halt the TIDE study because it would be unethical to continue the study and subject people to a randomized trial that involved a drug ”where we know the risk and benefit is not established beyond pioglitazone.”

Dr. Kaul was among the panelists who supported continuing TIDE. ”If you stop the study, how else are you going to resolve this uncertainty,” he said. But he agrees with the FDA decision. “The FDA had to do what they did,” but pointed out that considerable controversy over the drug remains.

Dr. Jellinger also would have liked the TIDE study to continue, and found it “unusual” that the gold standard of clinical trials, the prospective randomized, controlled study, was trumped by studies like meta-analyses.

During the press briefing, Dr. Woodcock said that the signal of increased risk “has not been completely refuted by any evidence, so we think it is prudent to restrict access and make sure that those using and prescribing the medication are aware of the facts and make the choice in an informed manner.”

It will take several months to fully implement the REMS program, Dr. Joshua Sharfstein said during the briefing. Until then, “Patients who are taking rosiglitazone should continue to do so, and consult their physician to discuss the possibility of selecting another medication without this concern of cardiac ischemia,” said Dr. Sharfstein, FDA’s principal deputy commissioner. “Once the REMS is in place, physicians will need to enroll patients before they can continue to receive the drug.”

When the REMS is active, Dr. Sharfstein reiterated, rosiglitazone will be available only to patients who cannot control their blood sugar on any other medication and who are unable to take pioglitazone for medical reasons. “Doctors will have to document this, and also that they have discussed the risks of rosiglitazone in order for the patient to receive the drug.”

Researchers had hoped the RECORD study would set the rosiglitazone risk story straight. But in July, the FDA panel tasked with reviewing the drug’s safety questioned RECORD and its adjudication of cardiovascular events. The independent review of RECORD’s adjudication at a patient record level will be done, Dr. Sharfstein said, “to catch events that occurred but which might have not been properly referred to the adjudication committee.”

In a press statement, Dr. Ellen Strahlman, GlaxoSmithKline’s chief medical officer, said, “Our primary concern continues to be patients with type 2 diabetes, and we are making every effort to ensure that physicians in Europe and the U.S. have all the information they need to help them understand how these regulatory decisions affect them and their patients.”

The statement noted that “the company continues to believe that [rosiglitazone] is an important treatment for patients with type 2 diabetes and is now working with the FDA and EMA to implement the required actions ... GSK will voluntarily cease promotion of [rosiglitazone] in all the countries in which it operates and will continue to respond to requests for information and support from healthcare professionals and patients.”

But other REMS programs – including the one that will be established for rosiglitazone – are much more restrictive, such as the one for the antiepileptic vigabatrin. That REMS requires not only a medication guide, but also a communication plan to ensure reporting of adverse events, elements to assure safe use, and a system to ensure that physicians, pharmacies, and patients who do not comply with the rules lose access to the drug.

Dr. Nissen has received research support from Takeda Pharmaceutical Co., AstraZeneca, Daiichi Sankyo Co., and several other pharmaceutical companies and has consulted for a many such companies without financial compensation. All payments from any for-profit entity are paid directly to charity. Dr. Rosen reports receiving a lecture fee from GlaxoSmithKline and grant support from Eli Lilly & Co., Merck & Co., and Novartis. Dr. Kaul has received research support from Hoffmann-La Roche and has been a consultant for that company as well as from Novo-Nordisk. Dr. Jellinger is on the speakers bureaus of Amylin Pharmaceuticals, Eli Lilly, Merck, Novo-Nordisk, Sanofi-Aventis, and Takeda.

Although the Food and Drug Administration’s decision to keep rosiglitazone on the market with a risk management program in place that preserves some access to the controversial diabetes drug, the plan is expected to squelch most prescribing and therefore, could have an effect that approaches that in Europe, where it will no longer be marketed.

Under a risk evaluation and mitigation strategy (REMS), rosiglitazone will be available only to new patients with type 2 diabetes who are unable to adequately manage their blood glucose on pioglitazone or are unable to take pioglitazone, the only other approved thiazolidinedione (TZD). However, patients who are already taking rosiglitazone may continue if, through the REMS program, they acknowledge their understanding of the drug’s potential cardiac risks, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said during a press briefing this week. About 600,000 U.S. patients are taking the drug; Dr. Woodcock said the REMS program will “significantly reduce” that number, while ensuring that those who continue will fully understand its potential risk.

Additionally, the FDA instructed the drug’s manufacturer, GlaxoSmithKline, to commission an independent readjudication of the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes) trial, which was submitted to the FDA in August 2009 and was undertaken to further explore cardiovascular safety signals seen in earlier trials.

At the same time, the European Medicines Agency announced it was pulling it off the shelves in the European Union, based on the same evidence reviewed by the FDA.

The FDA’s decision reflects the majority opinion of an FDA advisory panel, which in July met to review the cardiovascular safety data of the drug. The majority of the panel members voted to keep the drug on the market but with more warnings and restrictions on its use, but a significant proportion advocated that it should be taken off the market.

Rosiglitazone has been dogged for years by conflicting data on its cardiovascular safety profile and the decision to restrict access came on the heels of an ever-increasing debate about rosiglitazone’s cardiovascular safety. The RECORD trial, sponsored by GlaxoSmithKline, found no increased risk in myocardial infarction, overall death, or cardiovascular death. But several trials came to conflicting conclusions about whether the drug increased the risk of MI; a highly touted 2007 meta-analysis of 42 studies concluded that it increased that risk by up to 43%, and the risk of cardiovascular death by up to 64% (N. Engl. J. Med. 2007;356:2457-71).

The lead author of the meta-analysis, Dr. Steven E. Nissen, a vocal advocate for the withdrawal of rosiglitazone from the market, said in an interview that both the FDA and EMA decisions will result in almost the same outcomes and that rosiglitazone will soon be rarely used.

Even though the FDA did not opt for market withdrawal, the drug in the United States “is essentially off the market,” as long as the REMS is well executed, which he expects it will be. “What you have to actually do in order to prescribe the drug now is you have to say you’ve tried every other diabetes drug, including pioglitazone, and the patient couldn’t tolerate them. There’s nobody that meets that description,” said Dr. Nissen, chairman of the department of cardiovascular medicine, Cleveland Clinic Foundation.

At the July panel meeting, Dr. Nissen told the panel and the FDA that, with another thiazolidinedione available as an alternative (pioglitazone), continued marketing of rosiglitazone could not be medically or ethically justified. But, in the interview, he was positive about the agency’s decision. His message to clinicians is to “stop using the drug, get people on something else, and move on.”

Endocrinologist Clifford Rosen agreed. “This effectively puts an end to rosiglitazone in the United States ... it will be very, very rare to have a patient on rosiglitazone,” said Dr. Rosen, professor of medicine at Tufts University, Boston, and senior scientist at Maine Medical Center, Scarborough. He was among the 10 panel members at the July meeting who voted in favor of allowing continued marketing but with more warnings in the label and restrictions in its use.

The FDA decision “basically puts an end to rosiglitazone prescriptions in the United States,” he said in an interview. “It’s almost impossible for an individual practitioner to write a prescription after spending 20 minutes talking about risk, having the patient sign an informed consent and then filling out forms to send to the FDA. It’s just not going to happen.”

Dr. Rosen added that he expects that most patients who are on the drug now will probably be switched to other drugs. “Maybe a few people who have been on it for a long time, feel great, and have good glucose control might stay on it, but those individuals still need to have full informed consent and have the risks explained to them.”

Keeping a patient on rosiglitazone under the REMS “will be an onerous task” and the use of the drug will be “minimal,” said Dr. Paul Jellinger, professor of clinical medicine, University of Miami, and past president of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Patients can easily be switched form rosiglitazone to pioglitazone, or a non-TZD drug, such as an incretin-based treatment, he said in an interview.

Dr. Jellinger said that he thought the FDA decision was appropriate and that the FDA acted on behalf of patient safety, based on substantial amount of data. Although there was “considerable uncertainty, there remains a potential risk and there is a signal that suggests there may be a relationship.”

One of the cardiologists on the panel in July, Dr. Sanjay Kaul of the Cedars-Sinai Heart Institute in Los Angeles, said in an interview that the FDA’s decision is “the right call to keep the drug accessible but with significant restrictions that have teeth.” The decision, though, “reflects the uncertainty in the evidence – it is insufficient to either implicate the drug or exonerate it.”

During the press briefing, Dr. Woodcock said, “We still believe there is considerable uncertainty about the magnitude of the cardiovascular risk.” RECORD was an open-label trial, “and it was determined that we can’t rely on those results, even though they did not show a significantly increased risk of cardiac harm. Therefore, the questions raised by the meta-analysis have not really been answered,” she said.

The FDA also decided to terminate the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, also sponsored by GlaxoSmithKline, which was designed to determine any difference in cardiovascular safety between rosiglitazone and pioglitazone. In July, the FDA put TIDE on a partial hold, allowing patient enrollment but not treatment. The panel had voted 19-11 to continue the TIDE trial, if rosiglitazone remained on the U.S. market.

Dr. Rosen, who was among those strongly opposed to continuing the study, lauded the decision to halt the TIDE study because it would be unethical to continue the study and subject people to a randomized trial that involved a drug ”where we know the risk and benefit is not established beyond pioglitazone.”

Dr. Kaul was among the panelists who supported continuing TIDE. ”If you stop the study, how else are you going to resolve this uncertainty,” he said. But he agrees with the FDA decision. “The FDA had to do what they did,” but pointed out that considerable controversy over the drug remains.

Dr. Jellinger also would have liked the TIDE study to continue, and found it “unusual” that the gold standard of clinical trials, the prospective randomized, controlled study, was trumped by studies like meta-analyses.

During the press briefing, Dr. Woodcock said that the signal of increased risk “has not been completely refuted by any evidence, so we think it is prudent to restrict access and make sure that those using and prescribing the medication are aware of the facts and make the choice in an informed manner.”

It will take several months to fully implement the REMS program, Dr. Joshua Sharfstein said during the briefing. Until then, “Patients who are taking rosiglitazone should continue to do so, and consult their physician to discuss the possibility of selecting another medication without this concern of cardiac ischemia,” said Dr. Sharfstein, FDA’s principal deputy commissioner. “Once the REMS is in place, physicians will need to enroll patients before they can continue to receive the drug.”

When the REMS is active, Dr. Sharfstein reiterated, rosiglitazone will be available only to patients who cannot control their blood sugar on any other medication and who are unable to take pioglitazone for medical reasons. “Doctors will have to document this, and also that they have discussed the risks of rosiglitazone in order for the patient to receive the drug.”

Researchers had hoped the RECORD study would set the rosiglitazone risk story straight. But in July, the FDA panel tasked with reviewing the drug’s safety questioned RECORD and its adjudication of cardiovascular events. The independent review of RECORD’s adjudication at a patient record level will be done, Dr. Sharfstein said, “to catch events that occurred but which might have not been properly referred to the adjudication committee.”

In a press statement, Dr. Ellen Strahlman, GlaxoSmithKline’s chief medical officer, said, “Our primary concern continues to be patients with type 2 diabetes, and we are making every effort to ensure that physicians in Europe and the U.S. have all the information they need to help them understand how these regulatory decisions affect them and their patients.”

The statement noted that “the company continues to believe that [rosiglitazone] is an important treatment for patients with type 2 diabetes and is now working with the FDA and EMA to implement the required actions ... GSK will voluntarily cease promotion of [rosiglitazone] in all the countries in which it operates and will continue to respond to requests for information and support from healthcare professionals and patients.”

But other REMS programs – including the one that will be established for rosiglitazone – are much more restrictive, such as the one for the antiepileptic vigabatrin. That REMS requires not only a medication guide, but also a communication plan to ensure reporting of adverse events, elements to assure safe use, and a system to ensure that physicians, pharmacies, and patients who do not comply with the rules lose access to the drug.

Dr. Nissen has received research support from Takeda Pharmaceutical Co., AstraZeneca, Daiichi Sankyo Co., and several other pharmaceutical companies and has consulted for a many such companies without financial compensation. All payments from any for-profit entity are paid directly to charity. Dr. Rosen reports receiving a lecture fee from GlaxoSmithKline and grant support from Eli Lilly & Co., Merck & Co., and Novartis. Dr. Kaul has received research support from Hoffmann-La Roche and has been a consultant for that company as well as from Novo-Nordisk. Dr. Jellinger is on the speakers bureaus of Amylin Pharmaceuticals, Eli Lilly, Merck, Novo-Nordisk, Sanofi-Aventis, and Takeda.

SILVER SPRING, Md. – A Food and Drug Administration advisory panel on Sept. 20 unanimously voted to recommend that dabigatran, an orally administered direct thrombin inhibitor, be approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The panel based the decision on the results of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, a noninferiority, randomized international study of 18,113 patients with nonvalvular atrial fibrillation (AF) and at least one risk factor for stroke, which compared two blinded doses of dabigatran to open-label warfarin on the incidence of stroke and systemic embolism, the primary end point.

Both doses of dabigatran were considered noninferior to warfarin for preventing stroke and systemic embolism, and the 150 mg dose was more effective than warfarin and the 100 mg dose in preventing stroke and systemic embolism, according to the company, Boehringer Ingelheim Pharmaceuticals Inc. Both doses were associated with a reduction in hemorrhagic stroke and when compared to warfarin, the vascular death risk was reduced with the higher dose.

Compared to warfarin, the 150 mg dose was associated with a significantly increased risk of major GI bleeding, but also associated with a significant reduction in life-threatening and total bleeding. The 110 mg dose was also associated with a significant reduction in major, life-threatening, and total bleeding, when compared to warfarin. More patients on dabigatran had myocardial infarctions (1.4% and 1.5% among those on 110 mg and 150 mg, compared with 1.1% of those on warfarin).

The panel agreed that the study provided strong evidence that both dabigatran doses had been shown to be noninferior to warfarin therapy in the study, and several said they believed the 150 mg dose had been shown to be superior to warfarin.

Of the five cardiologists on the panel, three supported approval of the 150 mg dose only, because they were concerned that if both doses were available, clinicians might primarily prescribe the lower dose as the “default” dose because of fears over adverse events with the lower dose, and many patients would be deprived of a drug they considered more effective than warfarin.

Dabigatran was approved in 2008 in the European Union, Canada, Australia, Brazil and other countries for primary prevention of venous thromboembolic events in adults who have undergone elective be total hip replacement or total knee replacement surgery, according to Boehringer. It is marketed under the trade name Pradaxa, which will also be the trade name in the United States, if approved by the FDA.

The FDA’s decision is expected by Oct. 19. The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of disclosures related to the topic of the meeting, although occasionally, are granted waivers.

SILVER SPRING, Md. – A Food and Drug Administration advisory panel on Sept. 20 unanimously voted to recommend that dabigatran, an orally administered direct thrombin inhibitor, be approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The panel based the decision on the results of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, a noninferiority, randomized international study of 18,113 patients with nonvalvular atrial fibrillation (AF) and at least one risk factor for stroke, which compared two blinded doses of dabigatran to open-label warfarin on the incidence of stroke and systemic embolism, the primary end point.

Both doses of dabigatran were considered noninferior to warfarin for preventing stroke and systemic embolism, and the 150 mg dose was more effective than warfarin and the 100 mg dose in preventing stroke and systemic embolism, according to the company, Boehringer Ingelheim Pharmaceuticals Inc. Both doses were associated with a reduction in hemorrhagic stroke and when compared to warfarin, the vascular death risk was reduced with the higher dose.

Compared to warfarin, the 150 mg dose was associated with a significantly increased risk of major GI bleeding, but also associated with a significant reduction in life-threatening and total bleeding. The 110 mg dose was also associated with a significant reduction in major, life-threatening, and total bleeding, when compared to warfarin. More patients on dabigatran had myocardial infarctions (1.4% and 1.5% among those on 110 mg and 150 mg, compared with 1.1% of those on warfarin).

The panel agreed that the study provided strong evidence that both dabigatran doses had been shown to be noninferior to warfarin therapy in the study, and several said they believed the 150 mg dose had been shown to be superior to warfarin.

Of the five cardiologists on the panel, three supported approval of the 150 mg dose only, because they were concerned that if both doses were available, clinicians might primarily prescribe the lower dose as the “default” dose because of fears over adverse events with the lower dose, and many patients would be deprived of a drug they considered more effective than warfarin.

Dabigatran was approved in 2008 in the European Union, Canada, Australia, Brazil and other countries for primary prevention of venous thromboembolic events in adults who have undergone elective be total hip replacement or total knee replacement surgery, according to Boehringer. It is marketed under the trade name Pradaxa, which will also be the trade name in the United States, if approved by the FDA.

The FDA’s decision is expected by Oct. 19. The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of disclosures related to the topic of the meeting, although occasionally, are granted waivers.

SILVER SPRING, Md. – A Food and Drug Administration advisory panel on Sept. 20 unanimously voted to recommend that dabigatran, an orally administered direct thrombin inhibitor, be approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The panel based the decision on the results of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, a noninferiority, randomized international study of 18,113 patients with nonvalvular atrial fibrillation (AF) and at least one risk factor for stroke, which compared two blinded doses of dabigatran to open-label warfarin on the incidence of stroke and systemic embolism, the primary end point.

Both doses of dabigatran were considered noninferior to warfarin for preventing stroke and systemic embolism, and the 150 mg dose was more effective than warfarin and the 100 mg dose in preventing stroke and systemic embolism, according to the company, Boehringer Ingelheim Pharmaceuticals Inc. Both doses were associated with a reduction in hemorrhagic stroke and when compared to warfarin, the vascular death risk was reduced with the higher dose.

Compared to warfarin, the 150 mg dose was associated with a significantly increased risk of major GI bleeding, but also associated with a significant reduction in life-threatening and total bleeding. The 110 mg dose was also associated with a significant reduction in major, life-threatening, and total bleeding, when compared to warfarin. More patients on dabigatran had myocardial infarctions (1.4% and 1.5% among those on 110 mg and 150 mg, compared with 1.1% of those on warfarin).

The panel agreed that the study provided strong evidence that both dabigatran doses had been shown to be noninferior to warfarin therapy in the study, and several said they believed the 150 mg dose had been shown to be superior to warfarin.

Of the five cardiologists on the panel, three supported approval of the 150 mg dose only, because they were concerned that if both doses were available, clinicians might primarily prescribe the lower dose as the “default” dose because of fears over adverse events with the lower dose, and many patients would be deprived of a drug they considered more effective than warfarin.

Dabigatran was approved in 2008 in the European Union, Canada, Australia, Brazil and other countries for primary prevention of venous thromboembolic events in adults who have undergone elective be total hip replacement or total knee replacement surgery, according to Boehringer. It is marketed under the trade name Pradaxa, which will also be the trade name in the United States, if approved by the FDA.

The FDA’s decision is expected by Oct. 19. The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of disclosures related to the topic of the meeting, although occasionally, are granted waivers.

SILVER SPRING, Md. – A Food and Drug Administration advisory panel on Sept. 20 unanimously voted to recommend that dabigatran, an orally administered direct thrombin inhibitor, be approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The panel based the decision on the results of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, a noninferiority, randomized international study of 18,113 patients with nonvalvular atrial fibrillation (AF) and at least one risk factor for stroke, which compared two blinded doses of dabigatran to open-label warfarin on the incidence of stroke and systemic embolism, the primary end point.

Both doses of dabigatran were considered noninferior to warfarin for preventing stroke and systemic embolism, and the 150 mg dose was more effective than warfarin and the 100 mg dose in preventing stroke and systemic embolism, according to the company, Boehringer Ingelheim Pharmaceuticals Inc. Both doses were associated with a reduction in hemorrhagic stroke and when compared to warfarin, the vascular death risk was reduced with the higher dose.

Compared to warfarin, the 150 mg dose was associated with a significantly increased risk of major GI bleeding, but also associated with a significant reduction in life-threatening and total bleeding. The 110 mg dose was also associated with a significant reduction in major, life-threatening, and total bleeding, when compared to warfarin. More patients on dabigatran had myocardial infarctions (1.4% and 1.5% among those on 110 mg and 150 mg, compared with 1.1% of those on warfarin).

The panel agreed that the study provided strong evidence that both dabigatran doses had been shown to be noninferior to warfarin therapy in the study, and several said they believed the 150 mg dose had been shown to be superior to warfarin.

Of the five cardiologists on the panel, three supported approval of the 150 mg dose only, because they were concerned that if both doses were available, clinicians might primarily prescribe the lower dose as the “default” dose because of fears over adverse events with the lower dose, and many patients would be deprived of a drug they considered more effective than warfarin.

Dabigatran was approved in 2008 in the European Union, Canada, Australia, Brazil and other countries for primary prevention of venous thromboembolic events in adults who have undergone elective be total hip replacement or total knee replacement surgery, according to Boehringer. It is marketed under the trade name Pradaxa, which will also be the trade name in the United States, if approved by the FDA.

The FDA’s decision is expected by Oct. 19. The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of disclosures related to the topic of the meeting, although occasionally, are granted waivers.

SILVER SPRING, Md. – A Food and Drug Administration advisory panel on Sept. 20 unanimously voted to recommend that dabigatran, an orally administered direct thrombin inhibitor, be approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The panel based the decision on the results of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, a noninferiority, randomized international study of 18,113 patients with nonvalvular atrial fibrillation (AF) and at least one risk factor for stroke, which compared two blinded doses of dabigatran to open-label warfarin on the incidence of stroke and systemic embolism, the primary end point.

Both doses of dabigatran were considered noninferior to warfarin for preventing stroke and systemic embolism, and the 150 mg dose was more effective than warfarin and the 100 mg dose in preventing stroke and systemic embolism, according to the company, Boehringer Ingelheim Pharmaceuticals Inc. Both doses were associated with a reduction in hemorrhagic stroke and when compared to warfarin, the vascular death risk was reduced with the higher dose.

Compared to warfarin, the 150 mg dose was associated with a significantly increased risk of major GI bleeding, but also associated with a significant reduction in life-threatening and total bleeding. The 110 mg dose was also associated with a significant reduction in major, life-threatening, and total bleeding, when compared to warfarin. More patients on dabigatran had myocardial infarctions (1.4% and 1.5% among those on 110 mg and 150 mg, compared with 1.1% of those on warfarin).

The panel agreed that the study provided strong evidence that both dabigatran doses had been shown to be noninferior to warfarin therapy in the study, and several said they believed the 150 mg dose had been shown to be superior to warfarin.

Of the five cardiologists on the panel, three supported approval of the 150 mg dose only, because they were concerned that if both doses were available, clinicians might primarily prescribe the lower dose as the “default” dose because of fears over adverse events with the lower dose, and many patients would be deprived of a drug they considered more effective than warfarin.

Dabigatran was approved in 2008 in the European Union, Canada, Australia, Brazil and other countries for primary prevention of venous thromboembolic events in adults who have undergone elective be total hip replacement or total knee replacement surgery, according to Boehringer. It is marketed under the trade name Pradaxa, which will also be the trade name in the United States, if approved by the FDA.

The FDA’s decision is expected by Oct. 19. The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of disclosures related to the topic of the meeting, although occasionally, are granted waivers.

SILVER SPRING, Md. – A Food and Drug Administration advisory panel on Sept. 20 unanimously voted to recommend that dabigatran, an orally administered direct thrombin inhibitor, be approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The panel based the decision on the results of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, a noninferiority, randomized international study of 18,113 patients with nonvalvular atrial fibrillation (AF) and at least one risk factor for stroke, which compared two blinded doses of dabigatran to open-label warfarin on the incidence of stroke and systemic embolism, the primary end point.

Both doses of dabigatran were considered noninferior to warfarin for preventing stroke and systemic embolism, and the 150 mg dose was more effective than warfarin and the 100 mg dose in preventing stroke and systemic embolism, according to the company, Boehringer Ingelheim Pharmaceuticals Inc. Both doses were associated with a reduction in hemorrhagic stroke and when compared to warfarin, the vascular death risk was reduced with the higher dose.

Compared to warfarin, the 150 mg dose was associated with a significantly increased risk of major GI bleeding, but also associated with a significant reduction in life-threatening and total bleeding. The 110 mg dose was also associated with a significant reduction in major, life-threatening, and total bleeding, when compared to warfarin. More patients on dabigatran had myocardial infarctions (1.4% and 1.5% among those on 110 mg and 150 mg, compared with 1.1% of those on warfarin).

The panel agreed that the study provided strong evidence that both dabigatran doses had been shown to be noninferior to warfarin therapy in the study, and several said they believed the 150 mg dose had been shown to be superior to warfarin.

Of the five cardiologists on the panel, three supported approval of the 150 mg dose only, because they were concerned that if both doses were available, clinicians might primarily prescribe the lower dose as the “default” dose because of fears over adverse events with the lower dose, and many patients would be deprived of a drug they considered more effective than warfarin.

Dabigatran was approved in 2008 in the European Union, Canada, Australia, Brazil and other countries for primary prevention of venous thromboembolic events in adults who have undergone elective be total hip replacement or total knee replacement surgery, according to Boehringer. It is marketed under the trade name Pradaxa, which will also be the trade name in the United States, if approved by the FDA.

The FDA’s decision is expected by Oct. 19. The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of disclosures related to the topic of the meeting, although occasionally, are granted waivers.

ADELPHI, Md.  – A Food and Drug Administration advisory on Sept. 16 panel voted 9-5 that the potential risks of the serotoninergic drug lorcaserin outweighed its potential benefits as a long-term treatment for weight loss in overweight and obese people and, therefore, did not support approval.

At the meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee reviewed data from two phase III clinical trials of more than 7,000 obese and overweight patients, comparing 10 mg lorcaserin administered once or twice daily with placebo over 1-2 years, combined with lifestyle modifications. The manufacturer, Arena Pharmaceuticals Inc., has proposed that lorcaserin, a selective serotonin 5-HT2c agonist, be approved for weight loss and for maintenance of weight loss, in people with a body mass index of at least 30 kg/m2 or a BMI of at least 27 kg/m2 and at least one weight-related comorbid condition. Most of the patients in the phase III studies were women in their early 40s, whose mean weight was about 100 kg; about two-thirds were white, about 20% were black, and about 12% were Hispanic.

Patients treated with the 10-mg twice-daily dose – the dose proposed for approval – lost a mean of almost 6% of their body weight in both studies, compared with a mean loss of 2.2% and 2.8% in the placebo groups, which were statistically significant differences. But the mean percentage of body weight lost among treated patients was only 3%-3.7% more than that of placebo patients, and in one study that continued for a second year, patients on lorcaserin gained the weight back, the FDA pointed out.

Panelists who voted no on the risk-benefit question cited the modest weight-loss effect in a highly selected group of patients in the studies, whom they said did not represent the broader, real-world population of probable lorcaserin candidates.

The long list of exclusion criteria included a diagnosis of diabetes, recent episode of major depression or anxiety, and treatment with a serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor within the previous 1-2 years. The manufacturer is conducting a study comparing lorcaserin with placebo in 600 patients with diabetes, but the panel agreed that the study was too small to produce any useful data in this population.

Panelists were also concerned about the development of mammary tumors in rats exposed to the drug at doses close to therapeutic doses in humans and said that this issue needed to be studied further.

They were encouraged, however, that the modest weight loss in the studies was accompanied by modest improvements in weight-related comorbidities, blood pressure, lipids, and glycemic parameters.

Evidence of valvular heart disease on echocardiograms after 1 year of treatment was identified in about 2% of patients in both the treatment and placebo arms during the studies. But several panelists pointed out that, if approved, lorcaserin might be used in combination with another weight-loss drug, phentermine, which has been associated with drug-induced valvular heart disease. One of the cardiologists on the panel said that, if approved, patients on the drug should have a follow-up echocardiogram.

The FDA usually follows the recommendations of its advisory panels. Members of advisory panels have been cleared of potential conflicts related to the topic under discussion. Although in some cases, the FDA grants a waiver to a member with a potential conflict, this did not occur at this meeting.

ADELPHI, Md.  – A Food and Drug Administration advisory on Sept. 16 panel voted 9-5 that the potential risks of the serotoninergic drug lorcaserin outweighed its potential benefits as a long-term treatment for weight loss in overweight and obese people and, therefore, did not support approval.

At the meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee reviewed data from two phase III clinical trials of more than 7,000 obese and overweight patients, comparing 10 mg lorcaserin administered once or twice daily with placebo over 1-2 years, combined with lifestyle modifications. The manufacturer, Arena Pharmaceuticals Inc., has proposed that lorcaserin, a selective serotonin 5-HT2c agonist, be approved for weight loss and for maintenance of weight loss, in people with a body mass index of at least 30 kg/m2 or a BMI of at least 27 kg/m2 and at least one weight-related comorbid condition. Most of the patients in the phase III studies were women in their early 40s, whose mean weight was about 100 kg; about two-thirds were white, about 20% were black, and about 12% were Hispanic.

Patients treated with the 10-mg twice-daily dose – the dose proposed for approval – lost a mean of almost 6% of their body weight in both studies, compared with a mean loss of 2.2% and 2.8% in the placebo groups, which were statistically significant differences. But the mean percentage of body weight lost among treated patients was only 3%-3.7% more than that of placebo patients, and in one study that continued for a second year, patients on lorcaserin gained the weight back, the FDA pointed out.

Panelists who voted no on the risk-benefit question cited the modest weight-loss effect in a highly selected group of patients in the studies, whom they said did not represent the broader, real-world population of probable lorcaserin candidates.

The long list of exclusion criteria included a diagnosis of diabetes, recent episode of major depression or anxiety, and treatment with a serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor within the previous 1-2 years. The manufacturer is conducting a study comparing lorcaserin with placebo in 600 patients with diabetes, but the panel agreed that the study was too small to produce any useful data in this population.

Panelists were also concerned about the development of mammary tumors in rats exposed to the drug at doses close to therapeutic doses in humans and said that this issue needed to be studied further.

They were encouraged, however, that the modest weight loss in the studies was accompanied by modest improvements in weight-related comorbidities, blood pressure, lipids, and glycemic parameters.

Evidence of valvular heart disease on echocardiograms after 1 year of treatment was identified in about 2% of patients in both the treatment and placebo arms during the studies. But several panelists pointed out that, if approved, lorcaserin might be used in combination with another weight-loss drug, phentermine, which has been associated with drug-induced valvular heart disease. One of the cardiologists on the panel said that, if approved, patients on the drug should have a follow-up echocardiogram.

The FDA usually follows the recommendations of its advisory panels. Members of advisory panels have been cleared of potential conflicts related to the topic under discussion. Although in some cases, the FDA grants a waiver to a member with a potential conflict, this did not occur at this meeting.

ADELPHI, Md.  – A Food and Drug Administration advisory on Sept. 16 panel voted 9-5 that the potential risks of the serotoninergic drug lorcaserin outweighed its potential benefits as a long-term treatment for weight loss in overweight and obese people and, therefore, did not support approval.

At the meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee reviewed data from two phase III clinical trials of more than 7,000 obese and overweight patients, comparing 10 mg lorcaserin administered once or twice daily with placebo over 1-2 years, combined with lifestyle modifications. The manufacturer, Arena Pharmaceuticals Inc., has proposed that lorcaserin, a selective serotonin 5-HT2c agonist, be approved for weight loss and for maintenance of weight loss, in people with a body mass index of at least 30 kg/m2 or a BMI of at least 27 kg/m2 and at least one weight-related comorbid condition. Most of the patients in the phase III studies were women in their early 40s, whose mean weight was about 100 kg; about two-thirds were white, about 20% were black, and about 12% were Hispanic.

Patients treated with the 10-mg twice-daily dose – the dose proposed for approval – lost a mean of almost 6% of their body weight in both studies, compared with a mean loss of 2.2% and 2.8% in the placebo groups, which were statistically significant differences. But the mean percentage of body weight lost among treated patients was only 3%-3.7% more than that of placebo patients, and in one study that continued for a second year, patients on lorcaserin gained the weight back, the FDA pointed out.

Panelists who voted no on the risk-benefit question cited the modest weight-loss effect in a highly selected group of patients in the studies, whom they said did not represent the broader, real-world population of probable lorcaserin candidates.

The long list of exclusion criteria included a diagnosis of diabetes, recent episode of major depression or anxiety, and treatment with a serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor within the previous 1-2 years. The manufacturer is conducting a study comparing lorcaserin with placebo in 600 patients with diabetes, but the panel agreed that the study was too small to produce any useful data in this population.

Panelists were also concerned about the development of mammary tumors in rats exposed to the drug at doses close to therapeutic doses in humans and said that this issue needed to be studied further.

They were encouraged, however, that the modest weight loss in the studies was accompanied by modest improvements in weight-related comorbidities, blood pressure, lipids, and glycemic parameters.

Evidence of valvular heart disease on echocardiograms after 1 year of treatment was identified in about 2% of patients in both the treatment and placebo arms during the studies. But several panelists pointed out that, if approved, lorcaserin might be used in combination with another weight-loss drug, phentermine, which has been associated with drug-induced valvular heart disease. One of the cardiologists on the panel said that, if approved, patients on the drug should have a follow-up echocardiogram.

The FDA usually follows the recommendations of its advisory panels. Members of advisory panels have been cleared of potential conflicts related to the topic under discussion. Although in some cases, the FDA grants a waiver to a member with a potential conflict, this did not occur at this meeting.

ADELPHI, Md. – A Food and Drug Administration advisory panel split on whether to recommend that sibutramine be withdrawn from the market because of concerns over its cardiovascular safety.

Sibutramine is a norepinephrine reuptake inhibitor approved as a weight-loss agent in 1997.

At a Sept. 15 meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, held to discuss the results of a large cardiovascular outcomes study of the drug, 8 of the 16 panelists recommended that sibutramine be withdrawn from the U.S. market because of concerns over cardiovascular safety, its modest weight loss effect, and lack of evidence of health benefits associated with treatment. Another two panelists recommended that it remain on the market, with the addition of a boxed warning to the label warning that treatment is associated with an increased risk for cardiac events and that blood pressure and pulse need to be closely monitored in patients during treatment.

The remaining six panelists recommended that it be allowed to remain on the market with this boxed warning – as well as limiting the drug’s use by restricting its distribution.

Sibutramineis marketed as Meridia by Abbott Laboratories as a weight-loss agent in obese or overweight people.

The modest increases in heart rate and blood pressure associated with sibutramine treatment have been a concern since it was approved, and, in 2002, contraindications were added to the label for the following populations: patients with a history of cardiovascular disease, heart failure, tachycardia, peripheral artery disease, arrhythmias, and cerebrovascular disease; patients with inadequately controlled hypertension; and patients older than 65 years. These additions were made because of concerns over data indicating that the risk of MIs and strokes was increased in patients with cardiovascular disease treated with sibutramine.

These concerns prompted the Sibutramine Cardiovascular Outcomes trial (SCOUT), a randomized, double-blind trial that compared placebo to sibutramine in almost 10,000 obese men and women, aged 51-88 years, with pre-existing cardiovascular disease, type 2 diabetes, or both. The study was conducted at the request of European health authorities and was the focus of the Sept. 15 meeting.

Over a mean 3.4 years, the risk of nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death (the primary end point) was increased by 16% among those treated with sibutramine over those on placebo. The increased risk was driven by the greater rate of nonfatal MIs (4.1%) and nonfatal strokes (2.6%) among those on sibutramine, compared to those on placebo (3.2% and 1.9%, respectively); the risk of cardiovascular mortality was not increased. The risk of the nonfatal events was increased among sibutramine users with pre-existing cardiovascular disease and with cardiovascular disease and type 2 diabetes, but not among those with type 2 diabetes alone.

Abbott proposed a risk management plan to address the risks, which would include a single pharmacy and a boxed warning to reinforce the contraindications in people with a CVD history and dispensing of the drug from a single pharmacy, to ensure treatment is started only in appropriate patients.

The FDA usually follows the recommendations of its advisory panels. Members of advisory panels have been cleared of having conflicts related to the topic of meetings. Occasionally, the agency grants a waiver to a panelist who has conflicts, but not at this meeting.

ADELPHI, Md. – A Food and Drug Administration advisory panel split on whether to recommend that sibutramine be withdrawn from the market because of concerns over its cardiovascular safety.

Sibutramine is a norepinephrine reuptake inhibitor approved as a weight-loss agent in 1997.

At a Sept. 15 meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, held to discuss the results of a large cardiovascular outcomes study of the drug, 8 of the 16 panelists recommended that sibutramine be withdrawn from the U.S. market because of concerns over cardiovascular safety, its modest weight loss effect, and lack of evidence of health benefits associated with treatment. Another two panelists recommended that it remain on the market, with the addition of a boxed warning to the label warning that treatment is associated with an increased risk for cardiac events and that blood pressure and pulse need to be closely monitored in patients during treatment.

The remaining six panelists recommended that it be allowed to remain on the market with this boxed warning – as well as limiting the drug’s use by restricting its distribution.

Sibutramineis marketed as Meridia by Abbott Laboratories as a weight-loss agent in obese or overweight people.

The modest increases in heart rate and blood pressure associated with sibutramine treatment have been a concern since it was approved, and, in 2002, contraindications were added to the label for the following populations: patients with a history of cardiovascular disease, heart failure, tachycardia, peripheral artery disease, arrhythmias, and cerebrovascular disease; patients with inadequately controlled hypertension; and patients older than 65 years. These additions were made because of concerns over data indicating that the risk of MIs and strokes was increased in patients with cardiovascular disease treated with sibutramine.

These concerns prompted the Sibutramine Cardiovascular Outcomes trial (SCOUT), a randomized, double-blind trial that compared placebo to sibutramine in almost 10,000 obese men and women, aged 51-88 years, with pre-existing cardiovascular disease, type 2 diabetes, or both. The study was conducted at the request of European health authorities and was the focus of the Sept. 15 meeting.

Over a mean 3.4 years, the risk of nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death (the primary end point) was increased by 16% among those treated with sibutramine over those on placebo. The increased risk was driven by the greater rate of nonfatal MIs (4.1%) and nonfatal strokes (2.6%) among those on sibutramine, compared to those on placebo (3.2% and 1.9%, respectively); the risk of cardiovascular mortality was not increased. The risk of the nonfatal events was increased among sibutramine users with pre-existing cardiovascular disease and with cardiovascular disease and type 2 diabetes, but not among those with type 2 diabetes alone.

Abbott proposed a risk management plan to address the risks, which would include a single pharmacy and a boxed warning to reinforce the contraindications in people with a CVD history and dispensing of the drug from a single pharmacy, to ensure treatment is started only in appropriate patients.

The FDA usually follows the recommendations of its advisory panels. Members of advisory panels have been cleared of having conflicts related to the topic of meetings. Occasionally, the agency grants a waiver to a panelist who has conflicts, but not at this meeting.

ADELPHI, Md. – A Food and Drug Administration advisory panel split on whether to recommend that sibutramine be withdrawn from the market because of concerns over its cardiovascular safety.

Sibutramine is a norepinephrine reuptake inhibitor approved as a weight-loss agent in 1997.

At a Sept. 15 meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, held to discuss the results of a large cardiovascular outcomes study of the drug, 8 of the 16 panelists recommended that sibutramine be withdrawn from the U.S. market because of concerns over cardiovascular safety, its modest weight loss effect, and lack of evidence of health benefits associated with treatment. Another two panelists recommended that it remain on the market, with the addition of a boxed warning to the label warning that treatment is associated with an increased risk for cardiac events and that blood pressure and pulse need to be closely monitored in patients during treatment.

The remaining six panelists recommended that it be allowed to remain on the market with this boxed warning – as well as limiting the drug’s use by restricting its distribution.

Sibutramineis marketed as Meridia by Abbott Laboratories as a weight-loss agent in obese or overweight people.

The modest increases in heart rate and blood pressure associated with sibutramine treatment have been a concern since it was approved, and, in 2002, contraindications were added to the label for the following populations: patients with a history of cardiovascular disease, heart failure, tachycardia, peripheral artery disease, arrhythmias, and cerebrovascular disease; patients with inadequately controlled hypertension; and patients older than 65 years. These additions were made because of concerns over data indicating that the risk of MIs and strokes was increased in patients with cardiovascular disease treated with sibutramine.

These concerns prompted the Sibutramine Cardiovascular Outcomes trial (SCOUT), a randomized, double-blind trial that compared placebo to sibutramine in almost 10,000 obese men and women, aged 51-88 years, with pre-existing cardiovascular disease, type 2 diabetes, or both. The study was conducted at the request of European health authorities and was the focus of the Sept. 15 meeting.

Over a mean 3.4 years, the risk of nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death (the primary end point) was increased by 16% among those treated with sibutramine over those on placebo. The increased risk was driven by the greater rate of nonfatal MIs (4.1%) and nonfatal strokes (2.6%) among those on sibutramine, compared to those on placebo (3.2% and 1.9%, respectively); the risk of cardiovascular mortality was not increased. The risk of the nonfatal events was increased among sibutramine users with pre-existing cardiovascular disease and with cardiovascular disease and type 2 diabetes, but not among those with type 2 diabetes alone.

Abbott proposed a risk management plan to address the risks, which would include a single pharmacy and a boxed warning to reinforce the contraindications in people with a CVD history and dispensing of the drug from a single pharmacy, to ensure treatment is started only in appropriate patients.

The FDA usually follows the recommendations of its advisory panels. Members of advisory panels have been cleared of having conflicts related to the topic of meetings. Occasionally, the agency grants a waiver to a panelist who has conflicts, but not at this meeting.

Pegloticase, a recombinant formulation of porcine uricase, has been approved by the Food and Drug Administration for the treatment of chronic gout in adults who are refractory to conventional treatments, the agency announced on Sept. 14.

Pegloticase, which is administered intravenously every 2 weeks, is approved with a Risk Evaluation and Mitigation Strategy (REMS), which will include materials for health care practitioners and a patient medication guide that explain the risks of severe infusion and allergic reactions associated with treatment, the FDA said in its statement.

It will be marketed under the trade name Krystexxa, by Savient Pharmaceuticals Inc. About 3% of the 3 million adults who have gout do not benefit from conventional therapy, and pegloticase “offers an important new option for them,” Dr. Badrul Chowdhury, director of the division of pulmonary, allergy, and rheumatology products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement.

Uricase is an enzyme that lowers serum uric acid and is not produced by humans.

In two clinical trials of 212 patients with severe gout, treatment with pegloticase lowered uric acid levels and reduced deposits of uric acid crystals in joints and soft tissue, according to the FDA.

In June 2009, an FDA advisory panel recommended approval of the drug for treating refractory gout based on these studies, agreeing that it would meet an unmet medical need. At the meeting, several rheumatologists on the panel referred to the drug’s unique ability to reduce tophi in patients in clinical trials.

In the studies, one of every four patients had a severe allergic reaction to the infusion, so patients receiving an infusion of pegloticase should be pretreated with a corticosteroid and antihistamine to minimize the risks of allergic reactions. Because the drug was not studied in patients with heart failure, “physicians are also being warned to be cautious” about administering the drug to patients with heart failure, the statement said.

In a statement, Savient said that pegloticase would be available “later this year.”

Pegloticase, a recombinant formulation of porcine uricase, has been approved by the Food and Drug Administration for the treatment of chronic gout in adults who are refractory to conventional treatments, the agency announced on Sept. 14.

Pegloticase, which is administered intravenously every 2 weeks, is approved with a Risk Evaluation and Mitigation Strategy (REMS), which will include materials for health care practitioners and a patient medication guide that explain the risks of severe infusion and allergic reactions associated with treatment, the FDA said in its statement.

It will be marketed under the trade name Krystexxa, by Savient Pharmaceuticals Inc. About 3% of the 3 million adults who have gout do not benefit from conventional therapy, and pegloticase “offers an important new option for them,” Dr. Badrul Chowdhury, director of the division of pulmonary, allergy, and rheumatology products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement.

Uricase is an enzyme that lowers serum uric acid and is not produced by humans.

In two clinical trials of 212 patients with severe gout, treatment with pegloticase lowered uric acid levels and reduced deposits of uric acid crystals in joints and soft tissue, according to the FDA.

In June 2009, an FDA advisory panel recommended approval of the drug for treating refractory gout based on these studies, agreeing that it would meet an unmet medical need. At the meeting, several rheumatologists on the panel referred to the drug’s unique ability to reduce tophi in patients in clinical trials.

In the studies, one of every four patients had a severe allergic reaction to the infusion, so patients receiving an infusion of pegloticase should be pretreated with a corticosteroid and antihistamine to minimize the risks of allergic reactions. Because the drug was not studied in patients with heart failure, “physicians are also being warned to be cautious” about administering the drug to patients with heart failure, the statement said.

In a statement, Savient said that pegloticase would be available “later this year.”

Pegloticase, a recombinant formulation of porcine uricase, has been approved by the Food and Drug Administration for the treatment of chronic gout in adults who are refractory to conventional treatments, the agency announced on Sept. 14.

Pegloticase, which is administered intravenously every 2 weeks, is approved with a Risk Evaluation and Mitigation Strategy (REMS), which will include materials for health care practitioners and a patient medication guide that explain the risks of severe infusion and allergic reactions associated with treatment, the FDA said in its statement.

It will be marketed under the trade name Krystexxa, by Savient Pharmaceuticals Inc. About 3% of the 3 million adults who have gout do not benefit from conventional therapy, and pegloticase “offers an important new option for them,” Dr. Badrul Chowdhury, director of the division of pulmonary, allergy, and rheumatology products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement.

Uricase is an enzyme that lowers serum uric acid and is not produced by humans.

In two clinical trials of 212 patients with severe gout, treatment with pegloticase lowered uric acid levels and reduced deposits of uric acid crystals in joints and soft tissue, according to the FDA.

In June 2009, an FDA advisory panel recommended approval of the drug for treating refractory gout based on these studies, agreeing that it would meet an unmet medical need. At the meeting, several rheumatologists on the panel referred to the drug’s unique ability to reduce tophi in patients in clinical trials.

In the studies, one of every four patients had a severe allergic reaction to the infusion, so patients receiving an infusion of pegloticase should be pretreated with a corticosteroid and antihistamine to minimize the risks of allergic reactions. Because the drug was not studied in patients with heart failure, “physicians are also being warned to be cautious” about administering the drug to patients with heart failure, the statement said.

In a statement, Savient said that pegloticase would be available “later this year.”

Long-term treatment with bisphosphonates may be related to an increased risk of atypical femur fractures in patients, who may experience weeks or even months of pain before fracture diagnosis, according to the final report issued by a task force convened by the American Society of Bone and Mineral Research.

Courtesy of Dr. Joseph Lane/Journal of Bone and Mineral Research

The society convened the international, multidisciplinary task force to address reports of “atypical fractures of the subtrochanteric region of the hip and the femoral shaft” in patients on long-term bisphosphonate therapy. A statement issued by the society on Sept. 14 announcing the release of the report referred to it as “the most comprehensive scientific report to date” on this issue. The task force based its report on findings from a review of published and unpublished data, interviews with scientists at companies that manufacture these drugs, and Food and Drug Administration data.

The review included a review of 310 published case reports of patients (aged 36-92 years) with atypical subtrochanteric and femoral shaft fractures. Of these patients, 291 (94%) had been treated with bisphosphonates, mostly for osteoporosis. The median duration of treatment was 7 years, and most were treated for more than 5 years, according to the report, which points out that these fractures are rare, accounting for less than 1% of the overall rate of hip and femur fractures (J. Bone Miner. Res. 2010 Sept. 14 [doi:10.1002/jbmr.253]).

More than half of the patients with such femur fractures had experienced a prodrome of pain in the groin or thigh for weeks or months, and fractures were bilateral in more than 25% of the patients.

“We are concerned that there may be a relationship between these fractures and long-term bisphosphonate use and, although the risk is low, we want to make sure that people know about the warning signs,” the task force cochair and lead author of the report, Dr. Elizabeth Shane, said in the ASBMR statement. “Health professionals should know the warning signs of atypical femur fractures, and regularly ask patients on these drugs about groin or thigh pain,” added Dr. Shane, professor of medicine at Columbia University in New York.

She also recommended that every year, clinicians should evaluate whether bisphosphonate therapy is appropriate for patient on these drugs, and that that the drugs “should be reserved” for patients with Paget’s disease, patients with osteoporosis who are at high risk of fractures, and patients with certain cancers, she added.

In the statement, Dr. Shane also said that for the “vast majority of patients with osteoporosis, these drugs are an important weapon against fractures and their benefits far outweigh the risks of using them.”

The ASBMR task force recommendations include establishing an international registry of patients with these fractures, increasing research to determine whether bisphosphonates are the cause, and improving the labeling of these products so that health care professionals and patients are more aware of the potential for these fractures and the associated symptoms.

A statement issued by the FDA on Sept. 14 said that the agency “recommends that healthcare professionals be aware of the possible risk of unusual femur fractures in patients taking bisphosphonates. Patients should talk to their healthcare professional if they develop new thigh or groin pain so that they may be evaluated to rule out a femur fracture.”

These fractures remain rare. Findings from one study show that they account for 0.6 of every 1,000 fractures (CMAJ 2010;182:384-5).

Dr. Shane and other members of the task force disclosed relationships with manufacturers of bisphosphonates. Serious adverse events associated with bisphosphonates should be reported to the FDA’s MedWatch program.

Long-term treatment with bisphosphonates may be related to an increased risk of atypical femur fractures in patients, who may experience weeks or even months of pain before fracture diagnosis, according to the final report issued by a task force convened by the American Society of Bone and Mineral Research.

Courtesy of Dr. Joseph Lane/Journal of Bone and Mineral Research

The society convened the international, multidisciplinary task force to address reports of “atypical fractures of the subtrochanteric region of the hip and the femoral shaft” in patients on long-term bisphosphonate therapy. A statement issued by the society on Sept. 14 announcing the release of the report referred to it as “the most comprehensive scientific report to date” on this issue. The task force based its report on findings from a review of published and unpublished data, interviews with scientists at companies that manufacture these drugs, and Food and Drug Administration data.

The review included a review of 310 published case reports of patients (aged 36-92 years) with atypical subtrochanteric and femoral shaft fractures. Of these patients, 291 (94%) had been treated with bisphosphonates, mostly for osteoporosis. The median duration of treatment was 7 years, and most were treated for more than 5 years, according to the report, which points out that these fractures are rare, accounting for less than 1% of the overall rate of hip and femur fractures (J. Bone Miner. Res. 2010 Sept. 14 [doi:10.1002/jbmr.253]).

More than half of the patients with such femur fractures had experienced a prodrome of pain in the groin or thigh for weeks or months, and fractures were bilateral in more than 25% of the patients.

“We are concerned that there may be a relationship between these fractures and long-term bisphosphonate use and, although the risk is low, we want to make sure that people know about the warning signs,” the task force cochair and lead author of the report, Dr. Elizabeth Shane, said in the ASBMR statement. “Health professionals should know the warning signs of atypical femur fractures, and regularly ask patients on these drugs about groin or thigh pain,” added Dr. Shane, professor of medicine at Columbia University in New York.

She also recommended that every year, clinicians should evaluate whether bisphosphonate therapy is appropriate for patient on these drugs, and that that the drugs “should be reserved” for patients with Paget’s disease, patients with osteoporosis who are at high risk of fractures, and patients with certain cancers, she added.

In the statement, Dr. Shane also said that for the “vast majority of patients with osteoporosis, these drugs are an important weapon against fractures and their benefits far outweigh the risks of using them.”

The ASBMR task force recommendations include establishing an international registry of patients with these fractures, increasing research to determine whether bisphosphonates are the cause, and improving the labeling of these products so that health care professionals and patients are more aware of the potential for these fractures and the associated symptoms.

A statement issued by the FDA on Sept. 14 said that the agency “recommends that healthcare professionals be aware of the possible risk of unusual femur fractures in patients taking bisphosphonates. Patients should talk to their healthcare professional if they develop new thigh or groin pain so that they may be evaluated to rule out a femur fracture.”

These fractures remain rare. Findings from one study show that they account for 0.6 of every 1,000 fractures (CMAJ 2010;182:384-5).

Dr. Shane and other members of the task force disclosed relationships with manufacturers of bisphosphonates. Serious adverse events associated with bisphosphonates should be reported to the FDA’s MedWatch program.

Long-term treatment with bisphosphonates may be related to an increased risk of atypical femur fractures in patients, who may experience weeks or even months of pain before fracture diagnosis, according to the final report issued by a task force convened by the American Society of Bone and Mineral Research.

Courtesy of Dr. Joseph Lane/Journal of Bone and Mineral Research

The society convened the international, multidisciplinary task force to address reports of “atypical fractures of the subtrochanteric region of the hip and the femoral shaft” in patients on long-term bisphosphonate therapy. A statement issued by the society on Sept. 14 announcing the release of the report referred to it as “the most comprehensive scientific report to date” on this issue. The task force based its report on findings from a review of published and unpublished data, interviews with scientists at companies that manufacture these drugs, and Food and Drug Administration data.

The review included a review of 310 published case reports of patients (aged 36-92 years) with atypical subtrochanteric and femoral shaft fractures. Of these patients, 291 (94%) had been treated with bisphosphonates, mostly for osteoporosis. The median duration of treatment was 7 years, and most were treated for more than 5 years, according to the report, which points out that these fractures are rare, accounting for less than 1% of the overall rate of hip and femur fractures (J. Bone Miner. Res. 2010 Sept. 14 [doi:10.1002/jbmr.253]).

More than half of the patients with such femur fractures had experienced a prodrome of pain in the groin or thigh for weeks or months, and fractures were bilateral in more than 25% of the patients.

“We are concerned that there may be a relationship between these fractures and long-term bisphosphonate use and, although the risk is low, we want to make sure that people know about the warning signs,” the task force cochair and lead author of the report, Dr. Elizabeth Shane, said in the ASBMR statement. “Health professionals should know the warning signs of atypical femur fractures, and regularly ask patients on these drugs about groin or thigh pain,” added Dr. Shane, professor of medicine at Columbia University in New York.

She also recommended that every year, clinicians should evaluate whether bisphosphonate therapy is appropriate for patient on these drugs, and that that the drugs “should be reserved” for patients with Paget’s disease, patients with osteoporosis who are at high risk of fractures, and patients with certain cancers, she added.

In the statement, Dr. Shane also said that for the “vast majority of patients with osteoporosis, these drugs are an important weapon against fractures and their benefits far outweigh the risks of using them.”

The ASBMR task force recommendations include establishing an international registry of patients with these fractures, increasing research to determine whether bisphosphonates are the cause, and improving the labeling of these products so that health care professionals and patients are more aware of the potential for these fractures and the associated symptoms.

A statement issued by the FDA on Sept. 14 said that the agency “recommends that healthcare professionals be aware of the possible risk of unusual femur fractures in patients taking bisphosphonates. Patients should talk to their healthcare professional if they develop new thigh or groin pain so that they may be evaluated to rule out a femur fracture.”

These fractures remain rare. Findings from one study show that they account for 0.6 of every 1,000 fractures (CMAJ 2010;182:384-5).

Dr. Shane and other members of the task force disclosed relationships with manufacturers of bisphosphonates. Serious adverse events associated with bisphosphonates should be reported to the FDA’s MedWatch program.