Elizabeth Mechcatie

A risk-management plan will be required to address the ongoing problems of misuse, abuse, inappropriate prescribing, and accidental overdoses of certain opioid medications, the Food and Drug Administration announced.

The agency said that letters had been sent to 16 manufacturers of 24 opioid products stating that a Risk Evaluation and Mitigation Strategy (REMS)—which is intended to address serious risks, including fatalities associated with the improper use of these drugs—will be required for their products. The FDA has addressed this problem in the past, with efforts that have included adding warnings to the product labels, direct communications to prescribers, and working with other federal agencies.

“Despite these efforts, the rates of misuse and abuse and of accidental overdosages of opiates have risen over the past decade,” Dr. John Jenkins, director of the Office of New Drugs in the FDA's Center for Drug Evaluation and Research, said during a briefing. In 2007, 21 million prescriptions for these 24 products were dispensed to 3.7 million individual patients and were associated with “hundreds” of reports of deaths, he said.

Under legislation passed in 2007, the FDA can require a company to provide a REMS if the agency determines that such a plan is needed to ensure that the benefits of a drug outweigh its risks. The REMS may include a medication guide, provided to patients with each prescription filled; a patient package insert; and education of prescribers.

The opioid drugs on the FDA's list include fentanyl (Duragesic extended-release transdermal system), methadone (Dolophine tablets), oxycodone (OxyContin extended-release tablets), oxymorphone (Opana extended-release tablets), and several extended-release oral morphine products. These products are responsible for the greatest proportion of serious adverse events and deaths, according to Dr. Jenkins.

He emphasized that patients and physicians should follow the directions on the label. Although these products are intended only for people who experience moderate to severe pain, are opioid tolerant, and require around-the-clock pain relief, the FDA receives reports of adverse events in opioid-intolerant people who are inappropriately prescribed one of these products for conditions like a sprained ankle, he noted.

In an interview, Dr. Roy Altman, professor of rheumatology at the University of California, Los Angeles, noted that the majority of physicians tend not to use narcotics for chronic noncancer pain when indicated, because of legal ramifications, potential addiction risks, and other issues.

The agency will be holding several meetings to discuss the REMS plan for these products, and to obtain input from interested parties, including physicians, industry representatives, members of the pain- and addiction-treatment communities, and patient advocacy groups, beginning with a meeting on March 3 for manufacturers.

The full list of the drugs, along with the FDA's statement, is available at www.fda.gov/cder/drug/infopage/opioids/default.htmwww.fda.gov/MedWatch/report.htm

A risk-management plan will be required to address the ongoing problems of misuse, abuse, inappropriate prescribing, and accidental overdoses of certain opioid medications, the Food and Drug Administration announced.

The agency said that letters had been sent to 16 manufacturers of 24 opioid products stating that a Risk Evaluation and Mitigation Strategy (REMS)—which is intended to address serious risks, including fatalities associated with the improper use of these drugs—will be required for their products. The FDA has addressed this problem in the past, with efforts that have included adding warnings to the product labels, direct communications to prescribers, and working with other federal agencies.

“Despite these efforts, the rates of misuse and abuse and of accidental overdosages of opiates have risen over the past decade,” Dr. John Jenkins, director of the Office of New Drugs in the FDA's Center for Drug Evaluation and Research, said during a briefing. In 2007, 21 million prescriptions for these 24 products were dispensed to 3.7 million individual patients and were associated with “hundreds” of reports of deaths, he said.

Under legislation passed in 2007, the FDA can require a company to provide a REMS if the agency determines that such a plan is needed to ensure that the benefits of a drug outweigh its risks. The REMS may include a medication guide, provided to patients with each prescription filled; a patient package insert; and education of prescribers.

The opioid drugs on the FDA's list include fentanyl (Duragesic extended-release transdermal system), methadone (Dolophine tablets), oxycodone (OxyContin extended-release tablets), oxymorphone (Opana extended-release tablets), and several extended-release oral morphine products. These products are responsible for the greatest proportion of serious adverse events and deaths, according to Dr. Jenkins.

He emphasized that patients and physicians should follow the directions on the label. Although these products are intended only for people who experience moderate to severe pain, are opioid tolerant, and require around-the-clock pain relief, the FDA receives reports of adverse events in opioid-intolerant people who are inappropriately prescribed one of these products for conditions like a sprained ankle, he noted.

In an interview, Dr. Roy Altman, professor of rheumatology at the University of California, Los Angeles, noted that the majority of physicians tend not to use narcotics for chronic noncancer pain when indicated, because of legal ramifications, potential addiction risks, and other issues.

The agency will be holding several meetings to discuss the REMS plan for these products, and to obtain input from interested parties, including physicians, industry representatives, members of the pain- and addiction-treatment communities, and patient advocacy groups, beginning with a meeting on March 3 for manufacturers.

The full list of the drugs, along with the FDA's statement, is available at www.fda.gov/cder/drug/infopage/opioids/default.htmwww.fda.gov/MedWatch/report.htm

A risk-management plan will be required to address the ongoing problems of misuse, abuse, inappropriate prescribing, and accidental overdoses of certain opioid medications, the Food and Drug Administration announced.

The agency said that letters had been sent to 16 manufacturers of 24 opioid products stating that a Risk Evaluation and Mitigation Strategy (REMS)—which is intended to address serious risks, including fatalities associated with the improper use of these drugs—will be required for their products. The FDA has addressed this problem in the past, with efforts that have included adding warnings to the product labels, direct communications to prescribers, and working with other federal agencies.

“Despite these efforts, the rates of misuse and abuse and of accidental overdosages of opiates have risen over the past decade,” Dr. John Jenkins, director of the Office of New Drugs in the FDA's Center for Drug Evaluation and Research, said during a briefing. In 2007, 21 million prescriptions for these 24 products were dispensed to 3.7 million individual patients and were associated with “hundreds” of reports of deaths, he said.

Under legislation passed in 2007, the FDA can require a company to provide a REMS if the agency determines that such a plan is needed to ensure that the benefits of a drug outweigh its risks. The REMS may include a medication guide, provided to patients with each prescription filled; a patient package insert; and education of prescribers.

The opioid drugs on the FDA's list include fentanyl (Duragesic extended-release transdermal system), methadone (Dolophine tablets), oxycodone (OxyContin extended-release tablets), oxymorphone (Opana extended-release tablets), and several extended-release oral morphine products. These products are responsible for the greatest proportion of serious adverse events and deaths, according to Dr. Jenkins.

He emphasized that patients and physicians should follow the directions on the label. Although these products are intended only for people who experience moderate to severe pain, are opioid tolerant, and require around-the-clock pain relief, the FDA receives reports of adverse events in opioid-intolerant people who are inappropriately prescribed one of these products for conditions like a sprained ankle, he noted.

In an interview, Dr. Roy Altman, professor of rheumatology at the University of California, Los Angeles, noted that the majority of physicians tend not to use narcotics for chronic noncancer pain when indicated, because of legal ramifications, potential addiction risks, and other issues.

The agency will be holding several meetings to discuss the REMS plan for these products, and to obtain input from interested parties, including physicians, industry representatives, members of the pain- and addiction-treatment communities, and patient advocacy groups, beginning with a meeting on March 3 for manufacturers.

The full list of the drugs, along with the FDA's statement, is available at www.fda.gov/cder/drug/infopage/opioids/default.htmwww.fda.gov/MedWatch/report.htm

GAITHERSBURG, MD. — If the Food and Drug Administration agrees with an advisory panel's narrow recommendation to take Darvon and other products that contain propoxyphene off the market, the void may not make much difference to rheumatologists, who appear to be among the lowest prescribers of these products.

At a joint meeting of the FDA's Anesthetic and Life Support Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee last month, the panelists voted 14–12 that the risk-benefit profile on these products did not support their continued marketing for the treatment of patients with mild to moderate pain. The majority of panelists agreed that there was “marginal” or “modest” evidence at best indicating that propoxyphene, an opioid analgesic, was effective as monotherapy, or that propoxyphene plus acetaminophen was more effective than acetaminophen alone. Several panel members said they did not believe there was any evidence of efficacy for propoxyphene, either alone or in combination with acetaminophen.

The FDA held the meeting to review the safety of these products, first approved in 1957, in response to a Citizen's Petition filed by Public Citizen's Health Research Group in February 2006, calling for a phased withdrawal of all propoxyphene-containing products from the market.

Darvon and Darvocet (propoxyphene plus acetaminophen) are the branded versions of propoxyphene, which is a schedule IV drug. There are multiple generic formulations available. In the petition, the group maintained that the risks of these products outweigh their benefits, citing insufficient evidence that propoxyphene alone effectively alleviates pain and offers little, if any, added benefit when combined with acetaminophen. The petition states that propoxyphene and its main metabolite are cardiotoxic, and that it has a narrow therapeutic index and was associated with 2,110 reports of accidental deaths in the United States from 1981 through 1999.

Based on data from U.S. outpatient retail pharmacies presented by the FDA, rheumatologists wrote about 525,000 prescriptions for propoxyphene-acetaminophen in 2007 (2.4% of the total).

Propoxyphene “just simply is not a very good drug,” and has become less popular over the past few years, said Dr. Roy Altman, professor of rheumatology and immunology at the University of California, Los Angeles.

In an interview, Dr. Altman said that he has not used propoxyphene in more than a decade, “mostly because it's such a weak analgesic.” Moreover, because of the side effects associated with propoxyphene, a more potent analgesic effect would be needed to justify its use, he added. In fact, when he was at the University of Miami several years ago, these products were contraindicated in elderly patients because of the multiple central nervous system side effects—such as depression, depersonalization, drowsiness, and unsteadiness—in this population, so the outcome of the FDA panel meeting does not surprise him, nor would it surprise others in the geriatric community, he said, adding that the main reason these products remain in use now is because of the critical need for more analgesic options.

At the FDA meeting, Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, presented data from DAWN (Drug Abuse Warning Network), which received reports of 446 propoxyphene-related deaths from U.S. emergency departments in 2006, and 503 such reports in 2007. (DAWN, which collects data on drugs associated with emergency department visits or deaths, covers only a fraction of the U.S. population; during this time, the number of jurisdictions reporting to DAWN increased.)

Among the other data he presented were reports made to the medical examiner in Florida in 2007 (not included in the DAWN data), in which 314 deaths were related to propoxyphene; in 25% of the cases, the medical examiner concluded that the drug was the cause of death.

The panelists agreed there was no evidence that at therapeutic levels, propoxyphene has been associated with an increased risk for cardiotoxicity, largely because of an insufficient amount of data. However, the panel agreed that if propoxyphene remained on the market, the cardiotoxicity potential should be studied further—in studies that evaluate QT and EKG changes as well as in observational studies, including in elderly populations. The panel also recommended that the label should be changed to discourage chronic use, which has not been studied. The panel cited concerns over the lack of data on safety and efficacy in chronic use and use in the elderly.

Panelists were split on whether the lack of conclusive evidence on efficacy—most of which was from single-dose studies conducted in the 1970s—or on safety justified keeping these products available in the U.S. Sean Hennessy, Pharm.D., of the University of Pennsylvania, Philadelphia, said he voted no because in the “absence of benefit, no risk is acceptable.”

At the meeting, the FDA presented efficacy data from seven acute-pain, single-dose trials that compared propoxyphene alone with acetaminophen alone, with propoxyphene plus acetaminophen, and with placebo, as well as a review of the medical literature through December 2008. Based on a review of these data, the agency concluded that propoxy-phene had a weak analgesic effect in some of the acute-pain trials, and that the contribution of propoxyphene to the analgesic effects of acetaminophen was “variable across acute pain trials,” said Dr. Jin Chen, a medical officer in the FDA's Division of Anesthesia, Analgesia, and Rheumatology Products. There were no data on chronic pain submitted to the FDA, and there is insufficient information in the literature to make any conclusions about its analgesic effects with chronic use, he said.

Other data presented by FDA reviewers indicated that there are possible drug-drug interactions with CYP3A4 inhibitors, and that the pharmacokinetics of the drug are altered with hepatic and renal impairment and in the elderly. Animal data indicate that propoxyphene may affect cardiac conduction and toxicity, possibly through its effects on sodium and potassium channels. There also have been case reports of cardiac effects in humans, such as prolonged PR interval and QRS widening associated with drug concentrations that exceed the clinical therapeutic level.

But it is unclear whether the cardiac effects seen in nonclinical studies would be a risk in people who are taking therapeutic doses of propoxyphene-containing drugs, according to the FDA reviewers.

Of the 65 unduplicated adverse event reports associated with propoxyphene-containing products that were submitted to the FDA's Adverse Event Reporting System between 2006 and 2007, 17% (11 cases) were cardiac-related events—including 4 cases of bradycardia, 2 cases of cardiorespiratory arrest, and 2 cases of tachycardia—but 82% of the cardiac cases were confounded by other factors that made it difficult to attribute the report to the drug, according to the FDA. The other cases included accidental multiple drug overdoses in 14% (nine cases) and 18% that were psychiatry related, such as hallucinations or changes in mental status; 40% of the reports overall were in the elderly, and 18% overall were fatal accidental overdoses.

Panelist Dr. William Hiatt, professor of medicine at the University of Colorado, Denver, said that based on these efficacy data, it appears that acetaminophen and propoxyphene alone are more effective than placebo, but that the combination did not clearly exceed pain relief with either component alone in studies of a single dose in people with acute postoperative or postpartum pain.

He also cited preclinical evidence of possible cardiotoxicity, particularly its effect on sodium channels, and recommended that if the products remained on the market, clinical studies should be conducted to evaluate QT changes associated with the drug, and whether the drug increases the background risk of cardiac events in an elderly population.

The FDA usually follows the recommendations of its advisory panels, which are not binding.

GAITHERSBURG, MD. — If the Food and Drug Administration agrees with an advisory panel's narrow recommendation to take Darvon and other products that contain propoxyphene off the market, the void may not make much difference to rheumatologists, who appear to be among the lowest prescribers of these products.

At a joint meeting of the FDA's Anesthetic and Life Support Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee last month, the panelists voted 14–12 that the risk-benefit profile on these products did not support their continued marketing for the treatment of patients with mild to moderate pain. The majority of panelists agreed that there was “marginal” or “modest” evidence at best indicating that propoxyphene, an opioid analgesic, was effective as monotherapy, or that propoxyphene plus acetaminophen was more effective than acetaminophen alone. Several panel members said they did not believe there was any evidence of efficacy for propoxyphene, either alone or in combination with acetaminophen.

The FDA held the meeting to review the safety of these products, first approved in 1957, in response to a Citizen's Petition filed by Public Citizen's Health Research Group in February 2006, calling for a phased withdrawal of all propoxyphene-containing products from the market.

Darvon and Darvocet (propoxyphene plus acetaminophen) are the branded versions of propoxyphene, which is a schedule IV drug. There are multiple generic formulations available. In the petition, the group maintained that the risks of these products outweigh their benefits, citing insufficient evidence that propoxyphene alone effectively alleviates pain and offers little, if any, added benefit when combined with acetaminophen. The petition states that propoxyphene and its main metabolite are cardiotoxic, and that it has a narrow therapeutic index and was associated with 2,110 reports of accidental deaths in the United States from 1981 through 1999.

Based on data from U.S. outpatient retail pharmacies presented by the FDA, rheumatologists wrote about 525,000 prescriptions for propoxyphene-acetaminophen in 2007 (2.4% of the total).

Propoxyphene “just simply is not a very good drug,” and has become less popular over the past few years, said Dr. Roy Altman, professor of rheumatology and immunology at the University of California, Los Angeles.

In an interview, Dr. Altman said that he has not used propoxyphene in more than a decade, “mostly because it's such a weak analgesic.” Moreover, because of the side effects associated with propoxyphene, a more potent analgesic effect would be needed to justify its use, he added. In fact, when he was at the University of Miami several years ago, these products were contraindicated in elderly patients because of the multiple central nervous system side effects—such as depression, depersonalization, drowsiness, and unsteadiness—in this population, so the outcome of the FDA panel meeting does not surprise him, nor would it surprise others in the geriatric community, he said, adding that the main reason these products remain in use now is because of the critical need for more analgesic options.

At the FDA meeting, Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, presented data from DAWN (Drug Abuse Warning Network), which received reports of 446 propoxyphene-related deaths from U.S. emergency departments in 2006, and 503 such reports in 2007. (DAWN, which collects data on drugs associated with emergency department visits or deaths, covers only a fraction of the U.S. population; during this time, the number of jurisdictions reporting to DAWN increased.)

Among the other data he presented were reports made to the medical examiner in Florida in 2007 (not included in the DAWN data), in which 314 deaths were related to propoxyphene; in 25% of the cases, the medical examiner concluded that the drug was the cause of death.

The panelists agreed there was no evidence that at therapeutic levels, propoxyphene has been associated with an increased risk for cardiotoxicity, largely because of an insufficient amount of data. However, the panel agreed that if propoxyphene remained on the market, the cardiotoxicity potential should be studied further—in studies that evaluate QT and EKG changes as well as in observational studies, including in elderly populations. The panel also recommended that the label should be changed to discourage chronic use, which has not been studied. The panel cited concerns over the lack of data on safety and efficacy in chronic use and use in the elderly.

Panelists were split on whether the lack of conclusive evidence on efficacy—most of which was from single-dose studies conducted in the 1970s—or on safety justified keeping these products available in the U.S. Sean Hennessy, Pharm.D., of the University of Pennsylvania, Philadelphia, said he voted no because in the “absence of benefit, no risk is acceptable.”

At the meeting, the FDA presented efficacy data from seven acute-pain, single-dose trials that compared propoxyphene alone with acetaminophen alone, with propoxyphene plus acetaminophen, and with placebo, as well as a review of the medical literature through December 2008. Based on a review of these data, the agency concluded that propoxy-phene had a weak analgesic effect in some of the acute-pain trials, and that the contribution of propoxyphene to the analgesic effects of acetaminophen was “variable across acute pain trials,” said Dr. Jin Chen, a medical officer in the FDA's Division of Anesthesia, Analgesia, and Rheumatology Products. There were no data on chronic pain submitted to the FDA, and there is insufficient information in the literature to make any conclusions about its analgesic effects with chronic use, he said.

Other data presented by FDA reviewers indicated that there are possible drug-drug interactions with CYP3A4 inhibitors, and that the pharmacokinetics of the drug are altered with hepatic and renal impairment and in the elderly. Animal data indicate that propoxyphene may affect cardiac conduction and toxicity, possibly through its effects on sodium and potassium channels. There also have been case reports of cardiac effects in humans, such as prolonged PR interval and QRS widening associated with drug concentrations that exceed the clinical therapeutic level.

But it is unclear whether the cardiac effects seen in nonclinical studies would be a risk in people who are taking therapeutic doses of propoxyphene-containing drugs, according to the FDA reviewers.

Of the 65 unduplicated adverse event reports associated with propoxyphene-containing products that were submitted to the FDA's Adverse Event Reporting System between 2006 and 2007, 17% (11 cases) were cardiac-related events—including 4 cases of bradycardia, 2 cases of cardiorespiratory arrest, and 2 cases of tachycardia—but 82% of the cardiac cases were confounded by other factors that made it difficult to attribute the report to the drug, according to the FDA. The other cases included accidental multiple drug overdoses in 14% (nine cases) and 18% that were psychiatry related, such as hallucinations or changes in mental status; 40% of the reports overall were in the elderly, and 18% overall were fatal accidental overdoses.

Panelist Dr. William Hiatt, professor of medicine at the University of Colorado, Denver, said that based on these efficacy data, it appears that acetaminophen and propoxyphene alone are more effective than placebo, but that the combination did not clearly exceed pain relief with either component alone in studies of a single dose in people with acute postoperative or postpartum pain.

He also cited preclinical evidence of possible cardiotoxicity, particularly its effect on sodium channels, and recommended that if the products remained on the market, clinical studies should be conducted to evaluate QT changes associated with the drug, and whether the drug increases the background risk of cardiac events in an elderly population.

The FDA usually follows the recommendations of its advisory panels, which are not binding.

GAITHERSBURG, MD. — If the Food and Drug Administration agrees with an advisory panel's narrow recommendation to take Darvon and other products that contain propoxyphene off the market, the void may not make much difference to rheumatologists, who appear to be among the lowest prescribers of these products.

At a joint meeting of the FDA's Anesthetic and Life Support Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee last month, the panelists voted 14–12 that the risk-benefit profile on these products did not support their continued marketing for the treatment of patients with mild to moderate pain. The majority of panelists agreed that there was “marginal” or “modest” evidence at best indicating that propoxyphene, an opioid analgesic, was effective as monotherapy, or that propoxyphene plus acetaminophen was more effective than acetaminophen alone. Several panel members said they did not believe there was any evidence of efficacy for propoxyphene, either alone or in combination with acetaminophen.

The FDA held the meeting to review the safety of these products, first approved in 1957, in response to a Citizen's Petition filed by Public Citizen's Health Research Group in February 2006, calling for a phased withdrawal of all propoxyphene-containing products from the market.

Darvon and Darvocet (propoxyphene plus acetaminophen) are the branded versions of propoxyphene, which is a schedule IV drug. There are multiple generic formulations available. In the petition, the group maintained that the risks of these products outweigh their benefits, citing insufficient evidence that propoxyphene alone effectively alleviates pain and offers little, if any, added benefit when combined with acetaminophen. The petition states that propoxyphene and its main metabolite are cardiotoxic, and that it has a narrow therapeutic index and was associated with 2,110 reports of accidental deaths in the United States from 1981 through 1999.

Based on data from U.S. outpatient retail pharmacies presented by the FDA, rheumatologists wrote about 525,000 prescriptions for propoxyphene-acetaminophen in 2007 (2.4% of the total).

Propoxyphene “just simply is not a very good drug,” and has become less popular over the past few years, said Dr. Roy Altman, professor of rheumatology and immunology at the University of California, Los Angeles.

In an interview, Dr. Altman said that he has not used propoxyphene in more than a decade, “mostly because it's such a weak analgesic.” Moreover, because of the side effects associated with propoxyphene, a more potent analgesic effect would be needed to justify its use, he added. In fact, when he was at the University of Miami several years ago, these products were contraindicated in elderly patients because of the multiple central nervous system side effects—such as depression, depersonalization, drowsiness, and unsteadiness—in this population, so the outcome of the FDA panel meeting does not surprise him, nor would it surprise others in the geriatric community, he said, adding that the main reason these products remain in use now is because of the critical need for more analgesic options.

At the FDA meeting, Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, presented data from DAWN (Drug Abuse Warning Network), which received reports of 446 propoxyphene-related deaths from U.S. emergency departments in 2006, and 503 such reports in 2007. (DAWN, which collects data on drugs associated with emergency department visits or deaths, covers only a fraction of the U.S. population; during this time, the number of jurisdictions reporting to DAWN increased.)

Among the other data he presented were reports made to the medical examiner in Florida in 2007 (not included in the DAWN data), in which 314 deaths were related to propoxyphene; in 25% of the cases, the medical examiner concluded that the drug was the cause of death.

The panelists agreed there was no evidence that at therapeutic levels, propoxyphene has been associated with an increased risk for cardiotoxicity, largely because of an insufficient amount of data. However, the panel agreed that if propoxyphene remained on the market, the cardiotoxicity potential should be studied further—in studies that evaluate QT and EKG changes as well as in observational studies, including in elderly populations. The panel also recommended that the label should be changed to discourage chronic use, which has not been studied. The panel cited concerns over the lack of data on safety and efficacy in chronic use and use in the elderly.

Panelists were split on whether the lack of conclusive evidence on efficacy—most of which was from single-dose studies conducted in the 1970s—or on safety justified keeping these products available in the U.S. Sean Hennessy, Pharm.D., of the University of Pennsylvania, Philadelphia, said he voted no because in the “absence of benefit, no risk is acceptable.”

At the meeting, the FDA presented efficacy data from seven acute-pain, single-dose trials that compared propoxyphene alone with acetaminophen alone, with propoxyphene plus acetaminophen, and with placebo, as well as a review of the medical literature through December 2008. Based on a review of these data, the agency concluded that propoxy-phene had a weak analgesic effect in some of the acute-pain trials, and that the contribution of propoxyphene to the analgesic effects of acetaminophen was “variable across acute pain trials,” said Dr. Jin Chen, a medical officer in the FDA's Division of Anesthesia, Analgesia, and Rheumatology Products. There were no data on chronic pain submitted to the FDA, and there is insufficient information in the literature to make any conclusions about its analgesic effects with chronic use, he said.

Other data presented by FDA reviewers indicated that there are possible drug-drug interactions with CYP3A4 inhibitors, and that the pharmacokinetics of the drug are altered with hepatic and renal impairment and in the elderly. Animal data indicate that propoxyphene may affect cardiac conduction and toxicity, possibly through its effects on sodium and potassium channels. There also have been case reports of cardiac effects in humans, such as prolonged PR interval and QRS widening associated with drug concentrations that exceed the clinical therapeutic level.

But it is unclear whether the cardiac effects seen in nonclinical studies would be a risk in people who are taking therapeutic doses of propoxyphene-containing drugs, according to the FDA reviewers.

Of the 65 unduplicated adverse event reports associated with propoxyphene-containing products that were submitted to the FDA's Adverse Event Reporting System between 2006 and 2007, 17% (11 cases) were cardiac-related events—including 4 cases of bradycardia, 2 cases of cardiorespiratory arrest, and 2 cases of tachycardia—but 82% of the cardiac cases were confounded by other factors that made it difficult to attribute the report to the drug, according to the FDA. The other cases included accidental multiple drug overdoses in 14% (nine cases) and 18% that were psychiatry related, such as hallucinations or changes in mental status; 40% of the reports overall were in the elderly, and 18% overall were fatal accidental overdoses.

Panelist Dr. William Hiatt, professor of medicine at the University of Colorado, Denver, said that based on these efficacy data, it appears that acetaminophen and propoxyphene alone are more effective than placebo, but that the combination did not clearly exceed pain relief with either component alone in studies of a single dose in people with acute postoperative or postpartum pain.

He also cited preclinical evidence of possible cardiotoxicity, particularly its effect on sodium channels, and recommended that if the products remained on the market, clinical studies should be conducted to evaluate QT changes associated with the drug, and whether the drug increases the background risk of cardiac events in an elderly population.

The FDA usually follows the recommendations of its advisory panels, which are not binding.

SILVER SPRING, MD. — The influenza B strain in the current influenza vaccine in the United States should be replaced for the 2009-2010 influenza vaccine, according to a preliminary recommendation by a federal advisory panel, which based its decision on data on circulating viruses collected to date during this influenza season.

At a Feb. 18 meeting, the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee voted in favor of replacing the current B component of the vaccine, a B/Florida/4/2006-like virus (a B/Yamagata lineage virus), with a B/Brisbane/60/2008-like virus (a B/Victoria lineage virus).

The panelists unanimously voted to retain the two influenza A strains included in the current vaccine for the next season's vaccine. The influenza A (H1N1) strain in the current vaccine is an A/Brisbane/59/2007-like virus; the H3N2 strain is an A/Brisbane/10/2007-like virus. The panel's recommendations are not final; they will meet again to discuss the final recommendations later in the influenza season, taking into account data collected on influenza virus activity for the remainder of the season.

The panel's recommendations concur with those of the World Health Organization to retain the two influenza A strains, but to change the B strain to a B/Brisbane/60/2008-like virus, which reflects the B virus that is predominant worldwide.

On Feb. 24, the vaccine's use was endorsed for the upcoming influenza season by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention. The ACIP did not recommend any new age or risk groups be added to the list of those recommended to receive the vaccine, which currently includes 84% of the U.S. population. The remaining individuals—healthy adults aged 19-49 who are not close contacts of a child or other high-risk individual—are covered under the permissive recommendation for vaccination of “all individuals who want to reduce the risk of becoming ill with influenza or of transmitting it to others,” Dr. Anthony Fiore, of the CDC's influenza division, said at the ACIP meeting.

The ACIP did vote for some minor changes to its annual influenza statement, including removing the provisional “if feasible” phrase from the recommendation to vaccinate all children aged 6 months through 18 years and adding additional background information in support of vaccinating pregnant women and for routine vaccination of persons with vaccine indications during hospitalization. The ACIP also discussed the addition of information about ocular and respiratory symptoms following receipt of the injectable influenza vaccine (seen in less than 6% of recipients) to the statement's safety section, but postponed a vote on including that information until June, when more data are expected to be available.

At the FDA hearing, Alexander Klimov, Ph.D., noted that there are two major circulating lineages of influenza B viruses, Victoria and Yamagata. Worldwide, B viruses of both lineages (B/Victoria/2/87 and B/Yamagata/16/88 viruses) have cocirculated with H1N1 or H3N2 viruses, according to Dr. Klimov, chief of the virus surveillance and diagnosis branch, in the Centers for Disease Control and Prevention's influenza division. However, more than 60% of circulating B viruses are from B Victoria lineage, he said at the meeting.

During this season to date, influenza A (H1N1) viruses have predominated in the United States and in many other North American countries and in Asian countries, and the majority of the viruses have been closely related to the H1N1 strain included in the current vaccine, said Dr. Klimov, who is also deputy director of the WHO Collaborating Center for Surveillance, Epidemiology, and Control of Influenza.

Influenza A (H3N2) viruses have been cocirculating with H1N1 and B viruses in many countries, predominantly in most European countries and in Japan. Most have been antigenically similar to the H3N2 strain in the current vaccine, and have been sensitive to the influenza antivirals oseltamivir (Tamiflu) and zanamivir (Relenza), Dr. Klimov said.

In the United States, oseltamivir-resistant influenza A (H1N1) has predominated this season and has been found in 30 states, said Dr. Joseph Bresee of the epidemiology and prevention branch, in the CDC's influenza division. Oseltamivir-resistant H1N1 strains were antigenically similar or identical to the strains in the current vaccine. Viruses that have been sensitive to and those resistant to oseltamivir have been antigenically similar, he added.

This was the topic of a health advisory issued by the CDC in December, which recommended that zanamivir or a combination of oseltamivir and rimantadine (Flumadine) are more appropriate options than oseltamivir alone when influenza A (H1N1) virus infection or exposure is suspected.

SILVER SPRING, MD. — The influenza B strain in the current influenza vaccine in the United States should be replaced for the 2009-2010 influenza vaccine, according to a preliminary recommendation by a federal advisory panel, which based its decision on data on circulating viruses collected to date during this influenza season.

At a Feb. 18 meeting, the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee voted in favor of replacing the current B component of the vaccine, a B/Florida/4/2006-like virus (a B/Yamagata lineage virus), with a B/Brisbane/60/2008-like virus (a B/Victoria lineage virus).

The panelists unanimously voted to retain the two influenza A strains included in the current vaccine for the next season's vaccine. The influenza A (H1N1) strain in the current vaccine is an A/Brisbane/59/2007-like virus; the H3N2 strain is an A/Brisbane/10/2007-like virus. The panel's recommendations are not final; they will meet again to discuss the final recommendations later in the influenza season, taking into account data collected on influenza virus activity for the remainder of the season.

The panel's recommendations concur with those of the World Health Organization to retain the two influenza A strains, but to change the B strain to a B/Brisbane/60/2008-like virus, which reflects the B virus that is predominant worldwide.

On Feb. 24, the vaccine's use was endorsed for the upcoming influenza season by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention. The ACIP did not recommend any new age or risk groups be added to the list of those recommended to receive the vaccine, which currently includes 84% of the U.S. population. The remaining individuals—healthy adults aged 19-49 who are not close contacts of a child or other high-risk individual—are covered under the permissive recommendation for vaccination of “all individuals who want to reduce the risk of becoming ill with influenza or of transmitting it to others,” Dr. Anthony Fiore, of the CDC's influenza division, said at the ACIP meeting.

The ACIP did vote for some minor changes to its annual influenza statement, including removing the provisional “if feasible” phrase from the recommendation to vaccinate all children aged 6 months through 18 years and adding additional background information in support of vaccinating pregnant women and for routine vaccination of persons with vaccine indications during hospitalization. The ACIP also discussed the addition of information about ocular and respiratory symptoms following receipt of the injectable influenza vaccine (seen in less than 6% of recipients) to the statement's safety section, but postponed a vote on including that information until June, when more data are expected to be available.

At the FDA hearing, Alexander Klimov, Ph.D., noted that there are two major circulating lineages of influenza B viruses, Victoria and Yamagata. Worldwide, B viruses of both lineages (B/Victoria/2/87 and B/Yamagata/16/88 viruses) have cocirculated with H1N1 or H3N2 viruses, according to Dr. Klimov, chief of the virus surveillance and diagnosis branch, in the Centers for Disease Control and Prevention's influenza division. However, more than 60% of circulating B viruses are from B Victoria lineage, he said at the meeting.

During this season to date, influenza A (H1N1) viruses have predominated in the United States and in many other North American countries and in Asian countries, and the majority of the viruses have been closely related to the H1N1 strain included in the current vaccine, said Dr. Klimov, who is also deputy director of the WHO Collaborating Center for Surveillance, Epidemiology, and Control of Influenza.

Influenza A (H3N2) viruses have been cocirculating with H1N1 and B viruses in many countries, predominantly in most European countries and in Japan. Most have been antigenically similar to the H3N2 strain in the current vaccine, and have been sensitive to the influenza antivirals oseltamivir (Tamiflu) and zanamivir (Relenza), Dr. Klimov said.

In the United States, oseltamivir-resistant influenza A (H1N1) has predominated this season and has been found in 30 states, said Dr. Joseph Bresee of the epidemiology and prevention branch, in the CDC's influenza division. Oseltamivir-resistant H1N1 strains were antigenically similar or identical to the strains in the current vaccine. Viruses that have been sensitive to and those resistant to oseltamivir have been antigenically similar, he added.

This was the topic of a health advisory issued by the CDC in December, which recommended that zanamivir or a combination of oseltamivir and rimantadine (Flumadine) are more appropriate options than oseltamivir alone when influenza A (H1N1) virus infection or exposure is suspected.

SILVER SPRING, MD. — The influenza B strain in the current influenza vaccine in the United States should be replaced for the 2009-2010 influenza vaccine, according to a preliminary recommendation by a federal advisory panel, which based its decision on data on circulating viruses collected to date during this influenza season.

At a Feb. 18 meeting, the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee voted in favor of replacing the current B component of the vaccine, a B/Florida/4/2006-like virus (a B/Yamagata lineage virus), with a B/Brisbane/60/2008-like virus (a B/Victoria lineage virus).

The panelists unanimously voted to retain the two influenza A strains included in the current vaccine for the next season's vaccine. The influenza A (H1N1) strain in the current vaccine is an A/Brisbane/59/2007-like virus; the H3N2 strain is an A/Brisbane/10/2007-like virus. The panel's recommendations are not final; they will meet again to discuss the final recommendations later in the influenza season, taking into account data collected on influenza virus activity for the remainder of the season.

The panel's recommendations concur with those of the World Health Organization to retain the two influenza A strains, but to change the B strain to a B/Brisbane/60/2008-like virus, which reflects the B virus that is predominant worldwide.

On Feb. 24, the vaccine's use was endorsed for the upcoming influenza season by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention. The ACIP did not recommend any new age or risk groups be added to the list of those recommended to receive the vaccine, which currently includes 84% of the U.S. population. The remaining individuals—healthy adults aged 19-49 who are not close contacts of a child or other high-risk individual—are covered under the permissive recommendation for vaccination of “all individuals who want to reduce the risk of becoming ill with influenza or of transmitting it to others,” Dr. Anthony Fiore, of the CDC's influenza division, said at the ACIP meeting.

The ACIP did vote for some minor changes to its annual influenza statement, including removing the provisional “if feasible” phrase from the recommendation to vaccinate all children aged 6 months through 18 years and adding additional background information in support of vaccinating pregnant women and for routine vaccination of persons with vaccine indications during hospitalization. The ACIP also discussed the addition of information about ocular and respiratory symptoms following receipt of the injectable influenza vaccine (seen in less than 6% of recipients) to the statement's safety section, but postponed a vote on including that information until June, when more data are expected to be available.

At the FDA hearing, Alexander Klimov, Ph.D., noted that there are two major circulating lineages of influenza B viruses, Victoria and Yamagata. Worldwide, B viruses of both lineages (B/Victoria/2/87 and B/Yamagata/16/88 viruses) have cocirculated with H1N1 or H3N2 viruses, according to Dr. Klimov, chief of the virus surveillance and diagnosis branch, in the Centers for Disease Control and Prevention's influenza division. However, more than 60% of circulating B viruses are from B Victoria lineage, he said at the meeting.

During this season to date, influenza A (H1N1) viruses have predominated in the United States and in many other North American countries and in Asian countries, and the majority of the viruses have been closely related to the H1N1 strain included in the current vaccine, said Dr. Klimov, who is also deputy director of the WHO Collaborating Center for Surveillance, Epidemiology, and Control of Influenza.

Influenza A (H3N2) viruses have been cocirculating with H1N1 and B viruses in many countries, predominantly in most European countries and in Japan. Most have been antigenically similar to the H3N2 strain in the current vaccine, and have been sensitive to the influenza antivirals oseltamivir (Tamiflu) and zanamivir (Relenza), Dr. Klimov said.

In the United States, oseltamivir-resistant influenza A (H1N1) has predominated this season and has been found in 30 states, said Dr. Joseph Bresee of the epidemiology and prevention branch, in the CDC's influenza division. Oseltamivir-resistant H1N1 strains were antigenically similar or identical to the strains in the current vaccine. Viruses that have been sensitive to and those resistant to oseltamivir have been antigenically similar, he added.

This was the topic of a health advisory issued by the CDC in December, which recommended that zanamivir or a combination of oseltamivir and rimantadine (Flumadine) are more appropriate options than oseltamivir alone when influenza A (H1N1) virus infection or exposure is suspected.

Individuals who are genetically predisposed to obesity can prevent weight gain by being physically active, according to findings from a Finnish study of young adult twins.

The investigation involved more than 4,000 monozygotic and dizygotic twins, aged 22–27 years (average age 25), who were enrolled in a population-based longitudinal twin study.

Dr. Linda Mustelin of the University of Helsinki and her associates evaluated the impact of physical activity on the degree to which genetics influences body mass index and waist circumference, using quantitative genetic analyses of data from the twins and their families.

A high level of physical activity significantly modified the heritability of BMI and waist circumference, which they said was a new finding. Specifically, the analysis showed an inverse relationship between physical activity and waist circumference in males (r = −0.12) and females (r = −0.18), and between physical activity and BMI in females (r = −0.12).

The findings are consistent with previous studies suggesting that physical activity helps prevent obesity, but “most importantly, this study demonstrates that a physically active lifestyle is able to counteract genetic predisposition to obesity,” they concluded (Int. J. Obes. 2009;33:29–36).

Only a few studies have looked specifically at individuals with a genetic predisposition to obesity and the impact of physical activity on their weight.

They cited changes in expression patterns of genes regulating weight and adiposity as a possible mechanism.

Individuals who are genetically predisposed to obesity can prevent weight gain by being physically active, according to findings from a Finnish study of young adult twins.

The investigation involved more than 4,000 monozygotic and dizygotic twins, aged 22–27 years (average age 25), who were enrolled in a population-based longitudinal twin study.

Dr. Linda Mustelin of the University of Helsinki and her associates evaluated the impact of physical activity on the degree to which genetics influences body mass index and waist circumference, using quantitative genetic analyses of data from the twins and their families.

A high level of physical activity significantly modified the heritability of BMI and waist circumference, which they said was a new finding. Specifically, the analysis showed an inverse relationship between physical activity and waist circumference in males (r = −0.12) and females (r = −0.18), and between physical activity and BMI in females (r = −0.12).

The findings are consistent with previous studies suggesting that physical activity helps prevent obesity, but “most importantly, this study demonstrates that a physically active lifestyle is able to counteract genetic predisposition to obesity,” they concluded (Int. J. Obes. 2009;33:29–36).

Only a few studies have looked specifically at individuals with a genetic predisposition to obesity and the impact of physical activity on their weight.

They cited changes in expression patterns of genes regulating weight and adiposity as a possible mechanism.

Individuals who are genetically predisposed to obesity can prevent weight gain by being physically active, according to findings from a Finnish study of young adult twins.

The investigation involved more than 4,000 monozygotic and dizygotic twins, aged 22–27 years (average age 25), who were enrolled in a population-based longitudinal twin study.

Dr. Linda Mustelin of the University of Helsinki and her associates evaluated the impact of physical activity on the degree to which genetics influences body mass index and waist circumference, using quantitative genetic analyses of data from the twins and their families.

A high level of physical activity significantly modified the heritability of BMI and waist circumference, which they said was a new finding. Specifically, the analysis showed an inverse relationship between physical activity and waist circumference in males (r = −0.12) and females (r = −0.18), and between physical activity and BMI in females (r = −0.12).

The findings are consistent with previous studies suggesting that physical activity helps prevent obesity, but “most importantly, this study demonstrates that a physically active lifestyle is able to counteract genetic predisposition to obesity,” they concluded (Int. J. Obes. 2009;33:29–36).

Only a few studies have looked specifically at individuals with a genetic predisposition to obesity and the impact of physical activity on their weight.

They cited changes in expression patterns of genes regulating weight and adiposity as a possible mechanism.

SILVER SPRING, MD. — A Food and Drug Administration advisory panel voted unanimously to recommend that the antiplatelet drug prasugrel be approved for treating patients with acute coronary syndrome, who present with unstable angina, non-ST-segment elevation myocardial infarction, or ST elevation MI.

At a meeting this month, all nine voting members of the FDA's Cardiovascular and Renal Drugs Advisory Committee agreed that prasugrel—a drug that was shown to be more effective than clopidogrel in preventing cardiovascular events, but with a higher rate of serious bleeding in a study of more than 13,000 patients with acute coronary syndromes (ACS)—had a favorable benefit-to-risk profile.

Prasugrel is a thienopyridine, developed by Eli Lilly & Co. and Daiichi Sankyo Inc., which have proposed that it be approved for reducing cardiovascular events in patients with ACS, with unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI), when managed with PCI, and patients with STEMI when managed with primary or delayed percutaneous coronary intervention (PCI).

Prasugrel, administered as a 60-mg loading dose followed by 10 mg/day, was compared with clopidogrel, administered at a 300-mg loading dose followed by 75 mg/day, in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38), an international double-blind study of 13,608 patients with moderate to high-risk ACS, scheduled to have PCI. They had UA, NSTEMI, or STEMI. All patients were on aspirin.

Over a mean of 12 months, the primary end point, a composite of cardiovascular death, MI, or nonfatal stroke, occurred in 12.1% of the clopidogrel group, compared with 9.9% of the patients taking prasugrel, a significant reduction. Broken down by severity of presentation, the occurrence of the primary end point in the non-STEMI/UA group was 12% among those on clopidogrel, compared with 9.9% among those on prasugrel, a statistically significant difference. The rate in the STEMI group was 12.4% in those on clopidogrel, compared with 10.0% in those on prasugrel, also a significant difference.

The rate of strokes in both groups was 0.9%; the overall risk of cardiovascular death was also not significantly different between the two groups.

The main risk was bleeding. The rate of major bleeding was 2.2% in those on prasugrel, compared with 1.7% in those on clopidogrel; the rates of life-threatening bleeding, including fatalities, were 1.3% and 0.8%, respectively; fatal bleeding occurred in 0.3% a 0.1%; and intracranial hemorrhage rates were 0.3% and 0.2%. Bleeding most often occurred around the time of PCI, and was much higher after a coronary artery bypass graft (CABG).

The FDA's analysis of the overall risk-benefit profile of the drug showed that for every 1,000 patients with ACS treated with prasugrel, the treatment prevents 21 nonfatal MIs, three cardiovascular deaths, with no strokes, but at a cost of two fatal hemorrhages, three nonfatal major hemorrhages, five minor hemorrhages, and 19 minimal hemorrhages.

All panelists agreed that labeling should discourage physicians from prescribing prasugrel to treat patients with a history of stroke or TIA. Among patients over age 70 years, bleeding was not more common with prasugrel, but the sequelae were more serious.

The FDA usually follows the recommendations of its advisory committee. If approved, prasugrel will be marketed as Effient. Upon its approval, the company is ready to launch immediately, a company official said after the meeting.

SILVER SPRING, MD. — A Food and Drug Administration advisory panel voted unanimously to recommend that the antiplatelet drug prasugrel be approved for treating patients with acute coronary syndrome, who present with unstable angina, non-ST-segment elevation myocardial infarction, or ST elevation MI.

At a meeting this month, all nine voting members of the FDA's Cardiovascular and Renal Drugs Advisory Committee agreed that prasugrel—a drug that was shown to be more effective than clopidogrel in preventing cardiovascular events, but with a higher rate of serious bleeding in a study of more than 13,000 patients with acute coronary syndromes (ACS)—had a favorable benefit-to-risk profile.

Prasugrel is a thienopyridine, developed by Eli Lilly & Co. and Daiichi Sankyo Inc., which have proposed that it be approved for reducing cardiovascular events in patients with ACS, with unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI), when managed with PCI, and patients with STEMI when managed with primary or delayed percutaneous coronary intervention (PCI).

Prasugrel, administered as a 60-mg loading dose followed by 10 mg/day, was compared with clopidogrel, administered at a 300-mg loading dose followed by 75 mg/day, in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38), an international double-blind study of 13,608 patients with moderate to high-risk ACS, scheduled to have PCI. They had UA, NSTEMI, or STEMI. All patients were on aspirin.

Over a mean of 12 months, the primary end point, a composite of cardiovascular death, MI, or nonfatal stroke, occurred in 12.1% of the clopidogrel group, compared with 9.9% of the patients taking prasugrel, a significant reduction. Broken down by severity of presentation, the occurrence of the primary end point in the non-STEMI/UA group was 12% among those on clopidogrel, compared with 9.9% among those on prasugrel, a statistically significant difference. The rate in the STEMI group was 12.4% in those on clopidogrel, compared with 10.0% in those on prasugrel, also a significant difference.

The rate of strokes in both groups was 0.9%; the overall risk of cardiovascular death was also not significantly different between the two groups.

The main risk was bleeding. The rate of major bleeding was 2.2% in those on prasugrel, compared with 1.7% in those on clopidogrel; the rates of life-threatening bleeding, including fatalities, were 1.3% and 0.8%, respectively; fatal bleeding occurred in 0.3% a 0.1%; and intracranial hemorrhage rates were 0.3% and 0.2%. Bleeding most often occurred around the time of PCI, and was much higher after a coronary artery bypass graft (CABG).

The FDA's analysis of the overall risk-benefit profile of the drug showed that for every 1,000 patients with ACS treated with prasugrel, the treatment prevents 21 nonfatal MIs, three cardiovascular deaths, with no strokes, but at a cost of two fatal hemorrhages, three nonfatal major hemorrhages, five minor hemorrhages, and 19 minimal hemorrhages.

All panelists agreed that labeling should discourage physicians from prescribing prasugrel to treat patients with a history of stroke or TIA. Among patients over age 70 years, bleeding was not more common with prasugrel, but the sequelae were more serious.

The FDA usually follows the recommendations of its advisory committee. If approved, prasugrel will be marketed as Effient. Upon its approval, the company is ready to launch immediately, a company official said after the meeting.

SILVER SPRING, MD. — A Food and Drug Administration advisory panel voted unanimously to recommend that the antiplatelet drug prasugrel be approved for treating patients with acute coronary syndrome, who present with unstable angina, non-ST-segment elevation myocardial infarction, or ST elevation MI.

At a meeting this month, all nine voting members of the FDA's Cardiovascular and Renal Drugs Advisory Committee agreed that prasugrel—a drug that was shown to be more effective than clopidogrel in preventing cardiovascular events, but with a higher rate of serious bleeding in a study of more than 13,000 patients with acute coronary syndromes (ACS)—had a favorable benefit-to-risk profile.

Prasugrel is a thienopyridine, developed by Eli Lilly & Co. and Daiichi Sankyo Inc., which have proposed that it be approved for reducing cardiovascular events in patients with ACS, with unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI), when managed with PCI, and patients with STEMI when managed with primary or delayed percutaneous coronary intervention (PCI).

Prasugrel, administered as a 60-mg loading dose followed by 10 mg/day, was compared with clopidogrel, administered at a 300-mg loading dose followed by 75 mg/day, in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38), an international double-blind study of 13,608 patients with moderate to high-risk ACS, scheduled to have PCI. They had UA, NSTEMI, or STEMI. All patients were on aspirin.

Over a mean of 12 months, the primary end point, a composite of cardiovascular death, MI, or nonfatal stroke, occurred in 12.1% of the clopidogrel group, compared with 9.9% of the patients taking prasugrel, a significant reduction. Broken down by severity of presentation, the occurrence of the primary end point in the non-STEMI/UA group was 12% among those on clopidogrel, compared with 9.9% among those on prasugrel, a statistically significant difference. The rate in the STEMI group was 12.4% in those on clopidogrel, compared with 10.0% in those on prasugrel, also a significant difference.

The rate of strokes in both groups was 0.9%; the overall risk of cardiovascular death was also not significantly different between the two groups.

The main risk was bleeding. The rate of major bleeding was 2.2% in those on prasugrel, compared with 1.7% in those on clopidogrel; the rates of life-threatening bleeding, including fatalities, were 1.3% and 0.8%, respectively; fatal bleeding occurred in 0.3% a 0.1%; and intracranial hemorrhage rates were 0.3% and 0.2%. Bleeding most often occurred around the time of PCI, and was much higher after a coronary artery bypass graft (CABG).

The FDA's analysis of the overall risk-benefit profile of the drug showed that for every 1,000 patients with ACS treated with prasugrel, the treatment prevents 21 nonfatal MIs, three cardiovascular deaths, with no strokes, but at a cost of two fatal hemorrhages, three nonfatal major hemorrhages, five minor hemorrhages, and 19 minimal hemorrhages.

All panelists agreed that labeling should discourage physicians from prescribing prasugrel to treat patients with a history of stroke or TIA. Among patients over age 70 years, bleeding was not more common with prasugrel, but the sequelae were more serious.

The FDA usually follows the recommendations of its advisory committee. If approved, prasugrel will be marketed as Effient. Upon its approval, the company is ready to launch immediately, a company official said after the meeting.

Milnacipran, a selective serotonin and norepinephrine dual reuptake inhibitor, has been approved by the Food and Drug Administration for the management of fibromyalgia in adults, the third drug approved for this indication.

Approval was based on the results of two phase III studies of a total of 2,084 patients with fibromyalgia, which found that during 3-6 months of treatment, those (1,460 patients) treated with 100 mg or 200 mg of milnacipran per day experienced statistically significant and clinically meaningful improvements in pain, patient global assessment, and physical function, compared with those on placebo.

A 30% or greater improvement in pain scores at 15 weeks was reported by 56% of patients on the 200-mg dose and 53% on the 100-mg dose, both significantly better than the 41% on placebo.

Milnacipran is expected to be available in pharmacies in March, according to Forest Laboratories Inc. and Cypress Bioscience Inc., which will market it under the trade name Savella.

The FDA has determined that a Risk Evaluation and Mitigation Strategy (REMS) plan is necessary for milnacipran “to ensure that the benefits of the drug outweighs the risks,” according to the FDA's approval letter, which notes that the serious risks associated with drugs in this class are serious psychiatric symptoms, including suicidal ideation, particularly in patients with depression. The letter noted that patients with fibromyalgia often have other other mood disorders, such as major depression.

Milnacipran, a selective serotonin and norepinephrine dual reuptake inhibitor, has been approved by the Food and Drug Administration for the management of fibromyalgia in adults, the third drug approved for this indication.

Approval was based on the results of two phase III studies of a total of 2,084 patients with fibromyalgia, which found that during 3-6 months of treatment, those (1,460 patients) treated with 100 mg or 200 mg of milnacipran per day experienced statistically significant and clinically meaningful improvements in pain, patient global assessment, and physical function, compared with those on placebo.

A 30% or greater improvement in pain scores at 15 weeks was reported by 56% of patients on the 200-mg dose and 53% on the 100-mg dose, both significantly better than the 41% on placebo.

Milnacipran is expected to be available in pharmacies in March, according to Forest Laboratories Inc. and Cypress Bioscience Inc., which will market it under the trade name Savella.

The FDA has determined that a Risk Evaluation and Mitigation Strategy (REMS) plan is necessary for milnacipran “to ensure that the benefits of the drug outweighs the risks,” according to the FDA's approval letter, which notes that the serious risks associated with drugs in this class are serious psychiatric symptoms, including suicidal ideation, particularly in patients with depression. The letter noted that patients with fibromyalgia often have other other mood disorders, such as major depression.

Milnacipran, a selective serotonin and norepinephrine dual reuptake inhibitor, has been approved by the Food and Drug Administration for the management of fibromyalgia in adults, the third drug approved for this indication.

Approval was based on the results of two phase III studies of a total of 2,084 patients with fibromyalgia, which found that during 3-6 months of treatment, those (1,460 patients) treated with 100 mg or 200 mg of milnacipran per day experienced statistically significant and clinically meaningful improvements in pain, patient global assessment, and physical function, compared with those on placebo.

A 30% or greater improvement in pain scores at 15 weeks was reported by 56% of patients on the 200-mg dose and 53% on the 100-mg dose, both significantly better than the 41% on placebo.

Milnacipran is expected to be available in pharmacies in March, according to Forest Laboratories Inc. and Cypress Bioscience Inc., which will market it under the trade name Savella.

The FDA has determined that a Risk Evaluation and Mitigation Strategy (REMS) plan is necessary for milnacipran “to ensure that the benefits of the drug outweighs the risks,” according to the FDA's approval letter, which notes that the serious risks associated with drugs in this class are serious psychiatric symptoms, including suicidal ideation, particularly in patients with depression. The letter noted that patients with fibromyalgia often have other other mood disorders, such as major depression.

The advisory is available at: www.fda.gov/cder/drug/advisory/topical_anesthetics2009.htm

The use of topical lidocaine products to mitigate pain has the potential to cause life-threatening events, according to a public health advisory issued by the Food and Drug Administration Jan. 16.

"Before recommending a topical anesthetic for any purpose, doctors should determine if the desired amount of pain relief can be achieved safely with a topical anesthetic or if a different treatment would be more appropriate," the FDA alert says. If a topical anesthetic is considered the best choice, the lowest amount necessary to adequately relieve pain should be used, the agency recommends.

The advisory does not mention any reports of adverse events associated with the use of topical anesthetics in this context, but refers to a February 2007 FDA advisory that described two young women who died after applying a topical anesthetic to their legs after laser hair removal—and to a recently published study that evaluated the effect of lidocaine in relieving discomfort during mammograms (Radiology 2008;248:765-72).

In the study of 418 women aged 32-89 undergoing a screening mammogram, who expected to experience discomfort during the test, discomfort was significantly lower among those who were premedicated with 4% lidocaine gel, than among those premedicated with acetaminophen or ibuprofen.

In the study, topical lidocaine was spread over a wide area and covered with plastic, and no serious adverse effects were reported. But the FDA statement points out that the study was not large enough to determine whether this use could be associated with uncommon, serious reactions, and adds that the agency "remains concerned about the potential for topical anesthetics to cause serious and life-threatening adverse effects when applied to a large area of skin or when the area of application is covered."

When a topical anesthetic is recommended, patients need to apply the product sparingly, should avoid broken or irritated skin; and should be counseled that the risk of adverse effects is increased when a wrapping or dressing is used to cover the skin, the advisory recommends.

In the 2007 alert, the FDA said that in two separate incidents, women in their 20s had seizures and went into comas after applying topical products that contained a high concentration of lidocaine and tetracaine to their legs, and wrapped their legs in plastic wrap to increase the anesthetic effects.

The advisory is available at: www.fda.gov/cder/drug/advisory/topical_anesthetics2009.htm

The use of topical lidocaine products to mitigate pain has the potential to cause life-threatening events, according to a public health advisory issued by the Food and Drug Administration Jan. 16.

"Before recommending a topical anesthetic for any purpose, doctors should determine if the desired amount of pain relief can be achieved safely with a topical anesthetic or if a different treatment would be more appropriate," the FDA alert says. If a topical anesthetic is considered the best choice, the lowest amount necessary to adequately relieve pain should be used, the agency recommends.

The advisory does not mention any reports of adverse events associated with the use of topical anesthetics in this context, but refers to a February 2007 FDA advisory that described two young women who died after applying a topical anesthetic to their legs after laser hair removal—and to a recently published study that evaluated the effect of lidocaine in relieving discomfort during mammograms (Radiology 2008;248:765-72).

In the study of 418 women aged 32-89 undergoing a screening mammogram, who expected to experience discomfort during the test, discomfort was significantly lower among those who were premedicated with 4% lidocaine gel, than among those premedicated with acetaminophen or ibuprofen.

In the study, topical lidocaine was spread over a wide area and covered with plastic, and no serious adverse effects were reported. But the FDA statement points out that the study was not large enough to determine whether this use could be associated with uncommon, serious reactions, and adds that the agency "remains concerned about the potential for topical anesthetics to cause serious and life-threatening adverse effects when applied to a large area of skin or when the area of application is covered."

When a topical anesthetic is recommended, patients need to apply the product sparingly, should avoid broken or irritated skin; and should be counseled that the risk of adverse effects is increased when a wrapping or dressing is used to cover the skin, the advisory recommends.

In the 2007 alert, the FDA said that in two separate incidents, women in their 20s had seizures and went into comas after applying topical products that contained a high concentration of lidocaine and tetracaine to their legs, and wrapped their legs in plastic wrap to increase the anesthetic effects.

The advisory is available at: www.fda.gov/cder/drug/advisory/topical_anesthetics2009.htm

The use of topical lidocaine products to mitigate pain has the potential to cause life-threatening events, according to a public health advisory issued by the Food and Drug Administration Jan. 16.

"Before recommending a topical anesthetic for any purpose, doctors should determine if the desired amount of pain relief can be achieved safely with a topical anesthetic or if a different treatment would be more appropriate," the FDA alert says. If a topical anesthetic is considered the best choice, the lowest amount necessary to adequately relieve pain should be used, the agency recommends.

The advisory does not mention any reports of adverse events associated with the use of topical anesthetics in this context, but refers to a February 2007 FDA advisory that described two young women who died after applying a topical anesthetic to their legs after laser hair removal—and to a recently published study that evaluated the effect of lidocaine in relieving discomfort during mammograms (Radiology 2008;248:765-72).

In the study of 418 women aged 32-89 undergoing a screening mammogram, who expected to experience discomfort during the test, discomfort was significantly lower among those who were premedicated with 4% lidocaine gel, than among those premedicated with acetaminophen or ibuprofen.

In the study, topical lidocaine was spread over a wide area and covered with plastic, and no serious adverse effects were reported. But the FDA statement points out that the study was not large enough to determine whether this use could be associated with uncommon, serious reactions, and adds that the agency "remains concerned about the potential for topical anesthetics to cause serious and life-threatening adverse effects when applied to a large area of skin or when the area of application is covered."

When a topical anesthetic is recommended, patients need to apply the product sparingly, should avoid broken or irritated skin; and should be counseled that the risk of adverse effects is increased when a wrapping or dressing is used to cover the skin, the advisory recommends.

In the 2007 alert, the FDA said that in two separate incidents, women in their 20s had seizures and went into comas after applying topical products that contained a high concentration of lidocaine and tetracaine to their legs, and wrapped their legs in plastic wrap to increase the anesthetic effects.

The Food and Drug Administration has approved bimatoprost for increasing the growth of eyelashes, a side effect of the glaucoma-treating drug that was first observed several years ago in clinical trials.

The new indication for bimatoprost 0.03% ophthalmic solution is for “the treatment of hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness.” It will be marketed under the trade name Latisse by Allergan Inc., which markets the same product (Lumigan) for treating intraocular pressure in patients with open angle glaucoma or ocular hypertension. Lumigan was approved for glaucoma in 2001.

Unlike Lumigan, which is administered directly in the eye, Latisse is applied at night to the skin of the upper eyelid margin at the base of the eyelashes using a disposable applicator (one for each eye), which is to be used only once.

The new indication was approved on Dec. 26, 3 weeks after the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee met to review bimatoprost for the cosmetic indication. The panel unanimously agreed that the benefit-risk profile of bimatoprost for hypotrichosis of the eyelashes was favorable.

The panel decision was based on the efficacy data in a study comparing bimatoprost with a control vehicle in 278 people (aged 22-78 years) with hypotrichosis of the eyelashes, as well as a large bimatoprost safety database (SKIN & ALLERGY NEWS, January 2009, p. 1).

After 16 weeks, 78% of those in the bimatoprost group had at least a 1-point increase on a scale that measured eyelash prominence (the primary efficacy end point), compared with 18% of those on the vehicle, a statistically significant difference.

Exactly how bimatoprost, a prostaglandin analog, promotes eyelash growth has not been determined, but growth “is believed to occur by increasing the [percentage] of hairs in, and the duration of, the anagen or growth phase,” according to the labeling. Eye pruritus, conjunctival hyperemia, and skin hyperpigmentation are listed in the label as the most common adverse events, affecting about 3%-4% of people treated. Warnings include the possibility of pigmentation of the iris (which is likely to be permanent) and the eyelids.

Allergan has agreed to conduct a 4-month, randomized, controlled study of bimatoprost solution in at least 50 black subjects, according to the FDA's approval letter. The one black patient in the hypotrichosis study was in the vehicle group. Another postmarketing requirement is that the company conduct a study of the safety and efficacy of bimatoprost in patients aged 0-17 years with hypotrichosis.

Allergan plans to launch Latisse in the first quarter of 2009, according to a written statement from the company.

The Food and Drug Administration has approved bimatoprost for increasing the growth of eyelashes, a side effect of the glaucoma-treating drug that was first observed several years ago in clinical trials.

The new indication for bimatoprost 0.03% ophthalmic solution is for “the treatment of hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness.” It will be marketed under the trade name Latisse by Allergan Inc., which markets the same product (Lumigan) for treating intraocular pressure in patients with open angle glaucoma or ocular hypertension. Lumigan was approved for glaucoma in 2001.

Unlike Lumigan, which is administered directly in the eye, Latisse is applied at night to the skin of the upper eyelid margin at the base of the eyelashes using a disposable applicator (one for each eye), which is to be used only once.

The new indication was approved on Dec. 26, 3 weeks after the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee met to review bimatoprost for the cosmetic indication. The panel unanimously agreed that the benefit-risk profile of bimatoprost for hypotrichosis of the eyelashes was favorable.

The panel decision was based on the efficacy data in a study comparing bimatoprost with a control vehicle in 278 people (aged 22-78 years) with hypotrichosis of the eyelashes, as well as a large bimatoprost safety database (SKIN & ALLERGY NEWS, January 2009, p. 1).

After 16 weeks, 78% of those in the bimatoprost group had at least a 1-point increase on a scale that measured eyelash prominence (the primary efficacy end point), compared with 18% of those on the vehicle, a statistically significant difference.

Exactly how bimatoprost, a prostaglandin analog, promotes eyelash growth has not been determined, but growth “is believed to occur by increasing the [percentage] of hairs in, and the duration of, the anagen or growth phase,” according to the labeling. Eye pruritus, conjunctival hyperemia, and skin hyperpigmentation are listed in the label as the most common adverse events, affecting about 3%-4% of people treated. Warnings include the possibility of pigmentation of the iris (which is likely to be permanent) and the eyelids.

Allergan has agreed to conduct a 4-month, randomized, controlled study of bimatoprost solution in at least 50 black subjects, according to the FDA's approval letter. The one black patient in the hypotrichosis study was in the vehicle group. Another postmarketing requirement is that the company conduct a study of the safety and efficacy of bimatoprost in patients aged 0-17 years with hypotrichosis.

Allergan plans to launch Latisse in the first quarter of 2009, according to a written statement from the company.

The Food and Drug Administration has approved bimatoprost for increasing the growth of eyelashes, a side effect of the glaucoma-treating drug that was first observed several years ago in clinical trials.

The new indication for bimatoprost 0.03% ophthalmic solution is for “the treatment of hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness.” It will be marketed under the trade name Latisse by Allergan Inc., which markets the same product (Lumigan) for treating intraocular pressure in patients with open angle glaucoma or ocular hypertension. Lumigan was approved for glaucoma in 2001.

Unlike Lumigan, which is administered directly in the eye, Latisse is applied at night to the skin of the upper eyelid margin at the base of the eyelashes using a disposable applicator (one for each eye), which is to be used only once.

The new indication was approved on Dec. 26, 3 weeks after the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee met to review bimatoprost for the cosmetic indication. The panel unanimously agreed that the benefit-risk profile of bimatoprost for hypotrichosis of the eyelashes was favorable.

The panel decision was based on the efficacy data in a study comparing bimatoprost with a control vehicle in 278 people (aged 22-78 years) with hypotrichosis of the eyelashes, as well as a large bimatoprost safety database (SKIN & ALLERGY NEWS, January 2009, p. 1).

After 16 weeks, 78% of those in the bimatoprost group had at least a 1-point increase on a scale that measured eyelash prominence (the primary efficacy end point), compared with 18% of those on the vehicle, a statistically significant difference.

Exactly how bimatoprost, a prostaglandin analog, promotes eyelash growth has not been determined, but growth “is believed to occur by increasing the [percentage] of hairs in, and the duration of, the anagen or growth phase,” according to the labeling. Eye pruritus, conjunctival hyperemia, and skin hyperpigmentation are listed in the label as the most common adverse events, affecting about 3%-4% of people treated. Warnings include the possibility of pigmentation of the iris (which is likely to be permanent) and the eyelids.

Allergan has agreed to conduct a 4-month, randomized, controlled study of bimatoprost solution in at least 50 black subjects, according to the FDA's approval letter. The one black patient in the hypotrichosis study was in the vehicle group. Another postmarketing requirement is that the company conduct a study of the safety and efficacy of bimatoprost in patients aged 0-17 years with hypotrichosis.

Allergan plans to launch Latisse in the first quarter of 2009, according to a written statement from the company.

The Food and Drug Administration is investigating preliminary data indicating that people who have the human leukocyte antigen allele HLA-B*1052 may be at a greater risk of developing Stevens-Johnson syndrome and toxic epidermal necrolysis during treatment with phenytoin or fosphenytoin.

The allele is found “almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais,” the FDA announced in a posting on the agency's MedWatch site in November.

Until the FDA completes the evaluation, “health care providers should consider avoiding phenytoin and fosphenytoin as alternatives for carbamazepine in patients who test positive for HLA-B*1502,” the FDA advised.

In December 2007, the FDA announced that people of Asian ancestry with the same allele who were taking carbamazepine were at an increased risk of Stevens-Johnson syndrome (SJS) and and toxic epidermal necrolysis (TEN).

The label for carbamazepine now reads that testing for the allele is recommended when considering using carbamazepine in a patient who fits any of the categories, and that if it is present, it should not be used “unless the benefits clearly outweigh the risks,” according to the FDA.

However, because the potential risks associated with phenytoin and fosphenytoin still are being investigated, “there is not yet enough information to recommend testing” for the allele in patients of Asian ancestry being considered for treatment with one of these two antiepileptic drugs.

An estimated 10%–15% of people in parts of China, Thailand, Malaysia, Indonesia, the Philippines, and Taiwan may have this allele.

An average 2%–4% of South Asians, including Indians, “appear” to have the allele, but the rate may be higher in some groups, according to the statement from the agency.

The frequency of the allele appears to be low—less than 1%—among people in Japan and Korea.

The risk of serious skin reactions with these two drugs appears to be at its highest during the first months of treatment, which is also true for carbamazepine. More than 90% of people who have had a skin reaction with carbamazepine had it during the first months of treatment, whereas people who have been treated with the drug for a longer period “are at low risk of developing this reaction,” according to the FDA.

Phenytoin is marketed as Dilantin, Phenytex, and in generic formulations as well. Fosphenytoin, marketed as Cerebyx and also in generic formulations, is a prodrug of phenytoin.

The FDA is analyzing data from a study that reported that four of four Thai patients who developed SJS during treatment with phenytoin had the HLA-B*1502 allele.

However, only 18% of a control group of people who were able to tolerate phenytoin tested positive for the allele (Epilepsia 2008;49:2087–91).

The FDA said in its statement that it plans to provide updates on this issue as more information becomes available.

A link to the notice as well as related information is available at www.fda.gov/medwatch/safety/2008/safety08.htm#Phenytoin

Serious or unexpected adverse events associated with these drugs can be reported to MedWatch at 800–332–1088 or www.fda.gov/medwatch/report.htm

The Food and Drug Administration is investigating preliminary data indicating that people who have the human leukocyte antigen allele HLA-B*1052 may be at a greater risk of developing Stevens-Johnson syndrome and toxic epidermal necrolysis during treatment with phenytoin or fosphenytoin.

The allele is found “almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais,” the FDA announced in a posting on the agency's MedWatch site in November.

Until the FDA completes the evaluation, “health care providers should consider avoiding phenytoin and fosphenytoin as alternatives for carbamazepine in patients who test positive for HLA-B*1502,” the FDA advised.

In December 2007, the FDA announced that people of Asian ancestry with the same allele who were taking carbamazepine were at an increased risk of Stevens-Johnson syndrome (SJS) and and toxic epidermal necrolysis (TEN).

The label for carbamazepine now reads that testing for the allele is recommended when considering using carbamazepine in a patient who fits any of the categories, and that if it is present, it should not be used “unless the benefits clearly outweigh the risks,” according to the FDA.

However, because the potential risks associated with phenytoin and fosphenytoin still are being investigated, “there is not yet enough information to recommend testing” for the allele in patients of Asian ancestry being considered for treatment with one of these two antiepileptic drugs.

An estimated 10%–15% of people in parts of China, Thailand, Malaysia, Indonesia, the Philippines, and Taiwan may have this allele.

An average 2%–4% of South Asians, including Indians, “appear” to have the allele, but the rate may be higher in some groups, according to the statement from the agency.

The frequency of the allele appears to be low—less than 1%—among people in Japan and Korea.

The risk of serious skin reactions with these two drugs appears to be at its highest during the first months of treatment, which is also true for carbamazepine. More than 90% of people who have had a skin reaction with carbamazepine had it during the first months of treatment, whereas people who have been treated with the drug for a longer period “are at low risk of developing this reaction,” according to the FDA.

Phenytoin is marketed as Dilantin, Phenytex, and in generic formulations as well. Fosphenytoin, marketed as Cerebyx and also in generic formulations, is a prodrug of phenytoin.

The FDA is analyzing data from a study that reported that four of four Thai patients who developed SJS during treatment with phenytoin had the HLA-B*1502 allele.

However, only 18% of a control group of people who were able to tolerate phenytoin tested positive for the allele (Epilepsia 2008;49:2087–91).

The FDA said in its statement that it plans to provide updates on this issue as more information becomes available.

A link to the notice as well as related information is available at www.fda.gov/medwatch/safety/2008/safety08.htm#Phenytoin

Serious or unexpected adverse events associated with these drugs can be reported to MedWatch at 800–332–1088 or www.fda.gov/medwatch/report.htm

The Food and Drug Administration is investigating preliminary data indicating that people who have the human leukocyte antigen allele HLA-B*1052 may be at a greater risk of developing Stevens-Johnson syndrome and toxic epidermal necrolysis during treatment with phenytoin or fosphenytoin.

The allele is found “almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais,” the FDA announced in a posting on the agency's MedWatch site in November.

Until the FDA completes the evaluation, “health care providers should consider avoiding phenytoin and fosphenytoin as alternatives for carbamazepine in patients who test positive for HLA-B*1502,” the FDA advised.

In December 2007, the FDA announced that people of Asian ancestry with the same allele who were taking carbamazepine were at an increased risk of Stevens-Johnson syndrome (SJS) and and toxic epidermal necrolysis (TEN).

The label for carbamazepine now reads that testing for the allele is recommended when considering using carbamazepine in a patient who fits any of the categories, and that if it is present, it should not be used “unless the benefits clearly outweigh the risks,” according to the FDA.

However, because the potential risks associated with phenytoin and fosphenytoin still are being investigated, “there is not yet enough information to recommend testing” for the allele in patients of Asian ancestry being considered for treatment with one of these two antiepileptic drugs.

An estimated 10%–15% of people in parts of China, Thailand, Malaysia, Indonesia, the Philippines, and Taiwan may have this allele.

An average 2%–4% of South Asians, including Indians, “appear” to have the allele, but the rate may be higher in some groups, according to the statement from the agency.

The frequency of the allele appears to be low—less than 1%—among people in Japan and Korea.

The risk of serious skin reactions with these two drugs appears to be at its highest during the first months of treatment, which is also true for carbamazepine. More than 90% of people who have had a skin reaction with carbamazepine had it during the first months of treatment, whereas people who have been treated with the drug for a longer period “are at low risk of developing this reaction,” according to the FDA.

Phenytoin is marketed as Dilantin, Phenytex, and in generic formulations as well. Fosphenytoin, marketed as Cerebyx and also in generic formulations, is a prodrug of phenytoin.

The FDA is analyzing data from a study that reported that four of four Thai patients who developed SJS during treatment with phenytoin had the HLA-B*1502 allele.

However, only 18% of a control group of people who were able to tolerate phenytoin tested positive for the allele (Epilepsia 2008;49:2087–91).

The FDA said in its statement that it plans to provide updates on this issue as more information becomes available.

A link to the notice as well as related information is available at www.fda.gov/medwatch/safety/2008/safety08.htm#Phenytoin

Serious or unexpected adverse events associated with these drugs can be reported to MedWatch at 800–332–1088 or www.fda.gov/medwatch/report.htm

ROCKVILLE, MD. — The benefits of the single-ingredient, long-acting β-agonist products salmeterol (Serevent) and formoterol (Foradil) do not outweigh their risks when used for treating asthma in adults, adolescents, and children, according to a majority of the three Food and Drug Administration advisory panels who reviewed the safety of these drugs.

However, most of the panelists agreed that the benefits of Advair, which combines salmeterol with the inhaled corticosteroid (ICS) fluticasone, and Symbicort, which combines formoterol with the ICS budesonide, outweighed the risks when used to treat asthma in adults and adolescents, according to last month's joint meeting of the FDA's Pulmonary-Allergy Drugs Committee, Drug Safety and Risk Management Committee, and Pediatric Advisory Committee.

The panel members recommended that safety be further studied in randomized, controlled trials; that health care providers and patients be educated about the importance of using an ICS as the first-line treatment for asthma; and that a long-acting β-agonist (LABA) always be used in combination with an ICS.

Support for the use of Advair in children aged 4–11 years was mixed: The panels voted 13–11, with 3 abstentions, that Advair's benefits outweighed its risks for the maintenance treatment of asthma. Advair, marketed by GlaxoSmithKline, is approved for children aged 4 years and older. Symbicort is approved only for children aged 12 years and older, so the panels did not vote on the younger age group for this product.

The panelists' primary concern was that an LABA not be used as monotherapy for maintenance treatment in patients with asthma and that when an LABA is used, it always be combined with an ICS, reflecting current asthma treatment guidelines. Some panelists noted that the labeling for the single-ingredient products was not strong enough regarding the importance of combining them with an ICS for asthma. The panelists also agreed that more safety data were needed for children on Advair and Symbicort.

Panelist Dr. Fernando Martinez, director of the Arizona Respiratory Center at the University of Arizona, Tucson, said that “there's no doubt” that LABAs have improved the lives of children with asthma, and it would be “irresponsible” to withdraw them from the market. He said he has not prescribed monotherapy with an LABA alone for at least 5 years.

“I don't consider the benefits trivial at all,” said Dr. Jesse Joad, another pediatric pulmonologist on the panel, who described the advent of these drugs as a “revolution” in treating pediatric asthma. However, the single-ingredient products should not be used for asthma, said Dr. Joad, professor and vice chair of pediatrics at the University of California, Davis.

Serevent and Foradil also are approved for COPD, so they will remain on the market, but the warnings about not using them without an ICS in patients with asthma likely will be strengthened.

The three-panel meeting was held to review the risks and benefits of Serevent and Advair (marketed by GlaxoSmithKline), Foradil (marketed by Novartis), and Symbicort (marketed by AstraZeneca Pharmaceuticals LP). The companies presented their own analyses of data at the meeting.

The joint session took place nearly 6 years after the Salmeterol Multicenter Asthma Research Trial (SMART), a large, randomized, double-blind study comparing salmeterol inhalation aerosol with placebo in about 26,000 people with asthma over age 12 years (about 12% were 12–18 years old). SMART was stopped early, in January 2003, because of recruitment problems.

The study found a small but significant increase in asthma-related deaths after 28 weeks among those on salmeterol, compared with those on placebo (13 deaths vs. 3, a relative risk of 4.4); the risk appeared to be higher among blacks.

A paradoxical finding was that some severe events were increased while immediate symptoms were improved with treatment

At the most recent meeting, the FDA presented a new meta-analysis of data obtained from the manufacturers from 110 trials of Advair, Serevent (72% of subjects), Foradil, and Symbicort in about 61,000 people aged 4–100 years (median age 37). The median treatment time was about 6 months. About half of patients reported using an ICS at baseline.

Treatment with an LABA was associated with an increased risk of asthma-related events, compared with treatment that did not include an LABA (an ICS, short-acting β-agonist, or other non-LABA treatment), as measured by a composite end point of asthma-related deaths, asthma-related intubations, and asthma-related hospitalizations.

There were 20 asthma-related deaths: 16 in the LABA group (all in Serevent-treated patients) and 4 in the non-LABA group.

The increased risk associated with LABAs, as measured by the composite end point, was not seen with Advair.

Children aged 4–11 years appeared to be at the greatest risk, compared with other age groups. In addition, black patients were at a greater risk than other races, and women were at a greater risk than men.

For Advair, the panels voted 27–0 in favor of the benefit-risk profile for adults aged 18 years and older, and 23-3 with 1 abstention for adolescents aged 12–17 years.

For Symbicort the panel voted 26-0 with 1 abstention in favor of the benefit-risk profile in adults aged 18 years and older, and 20-5 with 2 abstentions for adolescents aged 12–17 years.

The panelists agreed that the benefits of Serevent did not outweigh its risks for maintenance treatment of asthma in adults by a vote of 17–10, in adolescents by a vote of 21-6, and in children aged 4–11 years by unanimous vote.

For Foradil, the panels agreed that the benefits did not outweigh its risks in adults by a vote of 18-9, and in adolescents by a vote of 21-6. The panels also unanimously agreed that the benefits of Foradil did not outweigh its risks in younger children.

The FDA usually follows the recommendations of its advisory panels, which are not binding.

ROCKVILLE, MD. — The benefits of the single-ingredient, long-acting β-agonist products salmeterol (Serevent) and formoterol (Foradil) do not outweigh their risks when used for treating asthma in adults, adolescents, and children, according to a majority of the three Food and Drug Administration advisory panels who reviewed the safety of these drugs.

However, most of the panelists agreed that the benefits of Advair, which combines salmeterol with the inhaled corticosteroid (ICS) fluticasone, and Symbicort, which combines formoterol with the ICS budesonide, outweighed the risks when used to treat asthma in adults and adolescents, according to last month's joint meeting of the FDA's Pulmonary-Allergy Drugs Committee, Drug Safety and Risk Management Committee, and Pediatric Advisory Committee.

The panel members recommended that safety be further studied in randomized, controlled trials; that health care providers and patients be educated about the importance of using an ICS as the first-line treatment for asthma; and that a long-acting β-agonist (LABA) always be used in combination with an ICS.

Support for the use of Advair in children aged 4–11 years was mixed: The panels voted 13–11, with 3 abstentions, that Advair's benefits outweighed its risks for the maintenance treatment of asthma. Advair, marketed by GlaxoSmithKline, is approved for children aged 4 years and older. Symbicort is approved only for children aged 12 years and older, so the panels did not vote on the younger age group for this product.

The panelists' primary concern was that an LABA not be used as monotherapy for maintenance treatment in patients with asthma and that when an LABA is used, it always be combined with an ICS, reflecting current asthma treatment guidelines. Some panelists noted that the labeling for the single-ingredient products was not strong enough regarding the importance of combining them with an ICS for asthma. The panelists also agreed that more safety data were needed for children on Advair and Symbicort.

Panelist Dr. Fernando Martinez, director of the Arizona Respiratory Center at the University of Arizona, Tucson, said that “there's no doubt” that LABAs have improved the lives of children with asthma, and it would be “irresponsible” to withdraw them from the market. He said he has not prescribed monotherapy with an LABA alone for at least 5 years.

“I don't consider the benefits trivial at all,” said Dr. Jesse Joad, another pediatric pulmonologist on the panel, who described the advent of these drugs as a “revolution” in treating pediatric asthma. However, the single-ingredient products should not be used for asthma, said Dr. Joad, professor and vice chair of pediatrics at the University of California, Davis.

Serevent and Foradil also are approved for COPD, so they will remain on the market, but the warnings about not using them without an ICS in patients with asthma likely will be strengthened.

The three-panel meeting was held to review the risks and benefits of Serevent and Advair (marketed by GlaxoSmithKline), Foradil (marketed by Novartis), and Symbicort (marketed by AstraZeneca Pharmaceuticals LP). The companies presented their own analyses of data at the meeting.

The joint session took place nearly 6 years after the Salmeterol Multicenter Asthma Research Trial (SMART), a large, randomized, double-blind study comparing salmeterol inhalation aerosol with placebo in about 26,000 people with asthma over age 12 years (about 12% were 12–18 years old). SMART was stopped early, in January 2003, because of recruitment problems.

The study found a small but significant increase in asthma-related deaths after 28 weeks among those on salmeterol, compared with those on placebo (13 deaths vs. 3, a relative risk of 4.4); the risk appeared to be higher among blacks.

A paradoxical finding was that some severe events were increased while immediate symptoms were improved with treatment

At the most recent meeting, the FDA presented a new meta-analysis of data obtained from the manufacturers from 110 trials of Advair, Serevent (72% of subjects), Foradil, and Symbicort in about 61,000 people aged 4–100 years (median age 37). The median treatment time was about 6 months. About half of patients reported using an ICS at baseline.

Treatment with an LABA was associated with an increased risk of asthma-related events, compared with treatment that did not include an LABA (an ICS, short-acting β-agonist, or other non-LABA treatment), as measured by a composite end point of asthma-related deaths, asthma-related intubations, and asthma-related hospitalizations.

There were 20 asthma-related deaths: 16 in the LABA group (all in Serevent-treated patients) and 4 in the non-LABA group.

The increased risk associated with LABAs, as measured by the composite end point, was not seen with Advair.

Children aged 4–11 years appeared to be at the greatest risk, compared with other age groups. In addition, black patients were at a greater risk than other races, and women were at a greater risk than men.

For Advair, the panels voted 27–0 in favor of the benefit-risk profile for adults aged 18 years and older, and 23-3 with 1 abstention for adolescents aged 12–17 years.

For Symbicort the panel voted 26-0 with 1 abstention in favor of the benefit-risk profile in adults aged 18 years and older, and 20-5 with 2 abstentions for adolescents aged 12–17 years.

The panelists agreed that the benefits of Serevent did not outweigh its risks for maintenance treatment of asthma in adults by a vote of 17–10, in adolescents by a vote of 21-6, and in children aged 4–11 years by unanimous vote.

For Foradil, the panels agreed that the benefits did not outweigh its risks in adults by a vote of 18-9, and in adolescents by a vote of 21-6. The panels also unanimously agreed that the benefits of Foradil did not outweigh its risks in younger children.

The FDA usually follows the recommendations of its advisory panels, which are not binding.

ROCKVILLE, MD. — The benefits of the single-ingredient, long-acting β-agonist products salmeterol (Serevent) and formoterol (Foradil) do not outweigh their risks when used for treating asthma in adults, adolescents, and children, according to a majority of the three Food and Drug Administration advisory panels who reviewed the safety of these drugs.

However, most of the panelists agreed that the benefits of Advair, which combines salmeterol with the inhaled corticosteroid (ICS) fluticasone, and Symbicort, which combines formoterol with the ICS budesonide, outweighed the risks when used to treat asthma in adults and adolescents, according to last month's joint meeting of the FDA's Pulmonary-Allergy Drugs Committee, Drug Safety and Risk Management Committee, and Pediatric Advisory Committee.

The panel members recommended that safety be further studied in randomized, controlled trials; that health care providers and patients be educated about the importance of using an ICS as the first-line treatment for asthma; and that a long-acting β-agonist (LABA) always be used in combination with an ICS.

Support for the use of Advair in children aged 4–11 years was mixed: The panels voted 13–11, with 3 abstentions, that Advair's benefits outweighed its risks for the maintenance treatment of asthma. Advair, marketed by GlaxoSmithKline, is approved for children aged 4 years and older. Symbicort is approved only for children aged 12 years and older, so the panels did not vote on the younger age group for this product.

The panelists' primary concern was that an LABA not be used as monotherapy for maintenance treatment in patients with asthma and that when an LABA is used, it always be combined with an ICS, reflecting current asthma treatment guidelines. Some panelists noted that the labeling for the single-ingredient products was not strong enough regarding the importance of combining them with an ICS for asthma. The panelists also agreed that more safety data were needed for children on Advair and Symbicort.

Panelist Dr. Fernando Martinez, director of the Arizona Respiratory Center at the University of Arizona, Tucson, said that “there's no doubt” that LABAs have improved the lives of children with asthma, and it would be “irresponsible” to withdraw them from the market. He said he has not prescribed monotherapy with an LABA alone for at least 5 years.

“I don't consider the benefits trivial at all,” said Dr. Jesse Joad, another pediatric pulmonologist on the panel, who described the advent of these drugs as a “revolution” in treating pediatric asthma. However, the single-ingredient products should not be used for asthma, said Dr. Joad, professor and vice chair of pediatrics at the University of California, Davis.

Serevent and Foradil also are approved for COPD, so they will remain on the market, but the warnings about not using them without an ICS in patients with asthma likely will be strengthened.

The three-panel meeting was held to review the risks and benefits of Serevent and Advair (marketed by GlaxoSmithKline), Foradil (marketed by Novartis), and Symbicort (marketed by AstraZeneca Pharmaceuticals LP). The companies presented their own analyses of data at the meeting.

The joint session took place nearly 6 years after the Salmeterol Multicenter Asthma Research Trial (SMART), a large, randomized, double-blind study comparing salmeterol inhalation aerosol with placebo in about 26,000 people with asthma over age 12 years (about 12% were 12–18 years old). SMART was stopped early, in January 2003, because of recruitment problems.

The study found a small but significant increase in asthma-related deaths after 28 weeks among those on salmeterol, compared with those on placebo (13 deaths vs. 3, a relative risk of 4.4); the risk appeared to be higher among blacks.

A paradoxical finding was that some severe events were increased while immediate symptoms were improved with treatment

At the most recent meeting, the FDA presented a new meta-analysis of data obtained from the manufacturers from 110 trials of Advair, Serevent (72% of subjects), Foradil, and Symbicort in about 61,000 people aged 4–100 years (median age 37). The median treatment time was about 6 months. About half of patients reported using an ICS at baseline.

Treatment with an LABA was associated with an increased risk of asthma-related events, compared with treatment that did not include an LABA (an ICS, short-acting β-agonist, or other non-LABA treatment), as measured by a composite end point of asthma-related deaths, asthma-related intubations, and asthma-related hospitalizations.

There were 20 asthma-related deaths: 16 in the LABA group (all in Serevent-treated patients) and 4 in the non-LABA group.

The increased risk associated with LABAs, as measured by the composite end point, was not seen with Advair.

Children aged 4–11 years appeared to be at the greatest risk, compared with other age groups. In addition, black patients were at a greater risk than other races, and women were at a greater risk than men.

For Advair, the panels voted 27–0 in favor of the benefit-risk profile for adults aged 18 years and older, and 23-3 with 1 abstention for adolescents aged 12–17 years.

For Symbicort the panel voted 26-0 with 1 abstention in favor of the benefit-risk profile in adults aged 18 years and older, and 20-5 with 2 abstentions for adolescents aged 12–17 years.

The panelists agreed that the benefits of Serevent did not outweigh its risks for maintenance treatment of asthma in adults by a vote of 17–10, in adolescents by a vote of 21-6, and in children aged 4–11 years by unanimous vote.

For Foradil, the panels agreed that the benefits did not outweigh its risks in adults by a vote of 18-9, and in adolescents by a vote of 21-6. The panels also unanimously agreed that the benefits of Foradil did not outweigh its risks in younger children.

The FDA usually follows the recommendations of its advisory panels, which are not binding.