Elizabeth Mechcatie

Disclosures: The study was funded by the National Institutes of Health.

The longer a woman breastfeeds, the less likely she will develop metabolic syndrome over time, even if she has a history of gestational diabetes, according to the results of a prospective study that followed almost 1,400 women for 20 years.

The study appeared online in Diabetes: The Journal of the American Diabetes Association (2009: [doi.org/10.2337/db09-1197]). It will be published in the print edition of the journal in February.

“Longer duration of lactation was associated with lower incidence of the metabolic syndrome years after delivery and post weaning” among the women who had developed gestational diabetes during pregnancy and those who had not, concluded the authors, who added that these associations could not be explained by lifestyle factors. Having breastfed for more than 1 month was associated with a 39%-46% lower incidence of metabolic syndrome (depending on duration of breastfeeding) among women with no history of gestational diabetes, and with a 44%-86% lower incidence among those with gestational diabetes.

“The findings indicate that breastfeeding a child may have lasting favorable effects on a woman's risk factors for later developing diabetes or heart disease,” the lead author, Erica P. Gunderson, Ph.D., said in a statement released by Kaiser Permanente.

Their findings did not appear to be caused by differences in weight gain, physical activity, or other health behaviors, but less abdominal fat and higher levels of high-density lipoprotein were characteristic of women who did not develop metabolic syndrome, added Dr. Gunderson of the division of research, epidemiology and prevention at Kaiser Permanente, Oakland, Calif. The study followed 1,399 women enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study, who were aged 18-30 years when they were enrolled, had never delivered a baby, and did not have metabolic syndrome at baseline. (CARDIA is a U.S. multicenter, population-based, observational study that is looking at the development of coronary heart disease risk factors in young black and white adults.)

Metabolic syndrome was defined using the National Cholesterol Education Program criteria for the diagnosis, which includes the presence of 3 of 5 characteristics that include waist girth over 88 cm, and a fasting triglyceride level of 150 mg/dL or more. Of these women, 704 had at least one singleton live birth in 1986-2006, including 84 who had gestational diabetes; over 20 years, 120 cases of metabolic syndrome were diagnosed among these women. The overall incidence of metabolic syndrome was 12.0 cases/1,000 person years. The incidence was significantly higher among those who had been diagnosed with gestational diabetes during pregnancy, than those who had not (22.1 cases/1,000 person years, compared with 10.8 cases/1,000 person years.)

“Among women with and without GDM [gestational diabetes mellitus] pregnancies, a longer cumulative duration of lactation was strongly protective, even after controlling for parity and baseline covariates, including components of metabolic syndrome before pregnancy,” the authors wrote. They noted that in previous studies, lactation has been found to have favorable effects on cardiometabolic risk factors in women with and without a history of gestational diabetes, but there have been few studies on whether these favorable effects persist and are protective after weaning.

They also pointed out that although lactation is associated with greater weight loss, changes in weight did not explain the association between lactation and metabolic syndrome that they found. More studies are needed to “elucidate the mechanisms through which lactation may influence women's cardiometabolic risk profiles, and whether lifestyle modifications, including lactation duration, may affect development of coronary heart dis ease and type 2 diabetes, particularly, among high-risk groups such as women with a history of GDM,” they wrote.

Disclosures: The study was funded by the National Institutes of Health.

The longer a woman breastfeeds, the less likely she will develop metabolic syndrome over time, even if she has a history of gestational diabetes, according to the results of a prospective study that followed almost 1,400 women for 20 years.

The study appeared online in Diabetes: The Journal of the American Diabetes Association (2009: [doi.org/10.2337/db09-1197]). It will be published in the print edition of the journal in February.

“Longer duration of lactation was associated with lower incidence of the metabolic syndrome years after delivery and post weaning” among the women who had developed gestational diabetes during pregnancy and those who had not, concluded the authors, who added that these associations could not be explained by lifestyle factors. Having breastfed for more than 1 month was associated with a 39%-46% lower incidence of metabolic syndrome (depending on duration of breastfeeding) among women with no history of gestational diabetes, and with a 44%-86% lower incidence among those with gestational diabetes.

“The findings indicate that breastfeeding a child may have lasting favorable effects on a woman's risk factors for later developing diabetes or heart disease,” the lead author, Erica P. Gunderson, Ph.D., said in a statement released by Kaiser Permanente.

Their findings did not appear to be caused by differences in weight gain, physical activity, or other health behaviors, but less abdominal fat and higher levels of high-density lipoprotein were characteristic of women who did not develop metabolic syndrome, added Dr. Gunderson of the division of research, epidemiology and prevention at Kaiser Permanente, Oakland, Calif. The study followed 1,399 women enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study, who were aged 18-30 years when they were enrolled, had never delivered a baby, and did not have metabolic syndrome at baseline. (CARDIA is a U.S. multicenter, population-based, observational study that is looking at the development of coronary heart disease risk factors in young black and white adults.)

Metabolic syndrome was defined using the National Cholesterol Education Program criteria for the diagnosis, which includes the presence of 3 of 5 characteristics that include waist girth over 88 cm, and a fasting triglyceride level of 150 mg/dL or more. Of these women, 704 had at least one singleton live birth in 1986-2006, including 84 who had gestational diabetes; over 20 years, 120 cases of metabolic syndrome were diagnosed among these women. The overall incidence of metabolic syndrome was 12.0 cases/1,000 person years. The incidence was significantly higher among those who had been diagnosed with gestational diabetes during pregnancy, than those who had not (22.1 cases/1,000 person years, compared with 10.8 cases/1,000 person years.)

“Among women with and without GDM [gestational diabetes mellitus] pregnancies, a longer cumulative duration of lactation was strongly protective, even after controlling for parity and baseline covariates, including components of metabolic syndrome before pregnancy,” the authors wrote. They noted that in previous studies, lactation has been found to have favorable effects on cardiometabolic risk factors in women with and without a history of gestational diabetes, but there have been few studies on whether these favorable effects persist and are protective after weaning.

They also pointed out that although lactation is associated with greater weight loss, changes in weight did not explain the association between lactation and metabolic syndrome that they found. More studies are needed to “elucidate the mechanisms through which lactation may influence women's cardiometabolic risk profiles, and whether lifestyle modifications, including lactation duration, may affect development of coronary heart dis ease and type 2 diabetes, particularly, among high-risk groups such as women with a history of GDM,” they wrote.

Disclosures: The study was funded by the National Institutes of Health.

The longer a woman breastfeeds, the less likely she will develop metabolic syndrome over time, even if she has a history of gestational diabetes, according to the results of a prospective study that followed almost 1,400 women for 20 years.

The study appeared online in Diabetes: The Journal of the American Diabetes Association (2009: [doi.org/10.2337/db09-1197]). It will be published in the print edition of the journal in February.

“Longer duration of lactation was associated with lower incidence of the metabolic syndrome years after delivery and post weaning” among the women who had developed gestational diabetes during pregnancy and those who had not, concluded the authors, who added that these associations could not be explained by lifestyle factors. Having breastfed for more than 1 month was associated with a 39%-46% lower incidence of metabolic syndrome (depending on duration of breastfeeding) among women with no history of gestational diabetes, and with a 44%-86% lower incidence among those with gestational diabetes.

“The findings indicate that breastfeeding a child may have lasting favorable effects on a woman's risk factors for later developing diabetes or heart disease,” the lead author, Erica P. Gunderson, Ph.D., said in a statement released by Kaiser Permanente.

Their findings did not appear to be caused by differences in weight gain, physical activity, or other health behaviors, but less abdominal fat and higher levels of high-density lipoprotein were characteristic of women who did not develop metabolic syndrome, added Dr. Gunderson of the division of research, epidemiology and prevention at Kaiser Permanente, Oakland, Calif. The study followed 1,399 women enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study, who were aged 18-30 years when they were enrolled, had never delivered a baby, and did not have metabolic syndrome at baseline. (CARDIA is a U.S. multicenter, population-based, observational study that is looking at the development of coronary heart disease risk factors in young black and white adults.)

Metabolic syndrome was defined using the National Cholesterol Education Program criteria for the diagnosis, which includes the presence of 3 of 5 characteristics that include waist girth over 88 cm, and a fasting triglyceride level of 150 mg/dL or more. Of these women, 704 had at least one singleton live birth in 1986-2006, including 84 who had gestational diabetes; over 20 years, 120 cases of metabolic syndrome were diagnosed among these women. The overall incidence of metabolic syndrome was 12.0 cases/1,000 person years. The incidence was significantly higher among those who had been diagnosed with gestational diabetes during pregnancy, than those who had not (22.1 cases/1,000 person years, compared with 10.8 cases/1,000 person years.)

“Among women with and without GDM [gestational diabetes mellitus] pregnancies, a longer cumulative duration of lactation was strongly protective, even after controlling for parity and baseline covariates, including components of metabolic syndrome before pregnancy,” the authors wrote. They noted that in previous studies, lactation has been found to have favorable effects on cardiometabolic risk factors in women with and without a history of gestational diabetes, but there have been few studies on whether these favorable effects persist and are protective after weaning.

They also pointed out that although lactation is associated with greater weight loss, changes in weight did not explain the association between lactation and metabolic syndrome that they found. More studies are needed to “elucidate the mechanisms through which lactation may influence women's cardiometabolic risk profiles, and whether lifestyle modifications, including lactation duration, may affect development of coronary heart dis ease and type 2 diabetes, particularly, among high-risk groups such as women with a history of GDM,” they wrote.

ROCKVILLE, MD. — Follow-up study of two biologics approved to treat juvenile idiopathic arthritis has not identified any new safety signals in pediatric patients that have not been previously identified in adults, a Food and Drug Administration official reported at a Dec. 8 committee meeting.

The FDA's Pediatric Advisory Committee heard updates from the agency on postmarketing safety data on abatacept, a selective T-cell costimulation modulator approved to treat JIA in children aged 6 years and older, and adalimumab, a tumor necrosis factor (TNF) blocker approved for treating JIA in children aged 4-17 years.

Abatacept, administered intravenously, is marketed as Orencia by Bristol-Myers Squibb Co. The company is conducting a 10-year pediatric safety study and is required by the FDA to establish a registry of 500 JIA patients who are treated with abatacept. The patients will be monitored for malignancies, other autoimmune diseases, and serious infections for 3 years. Between December 2005 and July 2009, there were seven reports of adverse events in children aged 7-16 years who were treated with abatacept, including one case of multiple sclerosis in a 14-year-old and lymphoma in a 16-year-old, which are listed in the label.

Adalimumab, administered subcutaneously, is marketed as Humira by Abbott Laboratories. Postmarketing requirements include conducting a 10-year safety study of the drug in 800 JIA patients aged 4-17 years.

In pediatric patients treated for at least 3 years, adverse events were similar in frequency and type to those reported in adults. But rates of hypersensitivity reactions and development of antibodies to adalimumab were higher among pediatric patients.

In August, the FDA reported an ongoing safety review, which suggested that pediatric patients who were treated with TNF blockers were at increased risk for lymphomas and other malignancies, including types rarely seen in children. A statement on this risk was added to the labels of all TNF blockers.

Since approval, 109 serious adverse events were reported in pediatric patients who were treated with adalimumab, of which 37 were cases of exposure in utero. There were two malignancies (lymphomas reported in a 16-year-old and a 10-year-old). Both patients had been on long-term treatment with other immunosuppressants, including other products associated with an increased malignancy risk.

ROCKVILLE, MD. — Follow-up study of two biologics approved to treat juvenile idiopathic arthritis has not identified any new safety signals in pediatric patients that have not been previously identified in adults, a Food and Drug Administration official reported at a Dec. 8 committee meeting.

The FDA's Pediatric Advisory Committee heard updates from the agency on postmarketing safety data on abatacept, a selective T-cell costimulation modulator approved to treat JIA in children aged 6 years and older, and adalimumab, a tumor necrosis factor (TNF) blocker approved for treating JIA in children aged 4-17 years.

Abatacept, administered intravenously, is marketed as Orencia by Bristol-Myers Squibb Co. The company is conducting a 10-year pediatric safety study and is required by the FDA to establish a registry of 500 JIA patients who are treated with abatacept. The patients will be monitored for malignancies, other autoimmune diseases, and serious infections for 3 years. Between December 2005 and July 2009, there were seven reports of adverse events in children aged 7-16 years who were treated with abatacept, including one case of multiple sclerosis in a 14-year-old and lymphoma in a 16-year-old, which are listed in the label.

Adalimumab, administered subcutaneously, is marketed as Humira by Abbott Laboratories. Postmarketing requirements include conducting a 10-year safety study of the drug in 800 JIA patients aged 4-17 years.

In pediatric patients treated for at least 3 years, adverse events were similar in frequency and type to those reported in adults. But rates of hypersensitivity reactions and development of antibodies to adalimumab were higher among pediatric patients.

In August, the FDA reported an ongoing safety review, which suggested that pediatric patients who were treated with TNF blockers were at increased risk for lymphomas and other malignancies, including types rarely seen in children. A statement on this risk was added to the labels of all TNF blockers.

Since approval, 109 serious adverse events were reported in pediatric patients who were treated with adalimumab, of which 37 were cases of exposure in utero. There were two malignancies (lymphomas reported in a 16-year-old and a 10-year-old). Both patients had been on long-term treatment with other immunosuppressants, including other products associated with an increased malignancy risk.

ROCKVILLE, MD. — Follow-up study of two biologics approved to treat juvenile idiopathic arthritis has not identified any new safety signals in pediatric patients that have not been previously identified in adults, a Food and Drug Administration official reported at a Dec. 8 committee meeting.

The FDA's Pediatric Advisory Committee heard updates from the agency on postmarketing safety data on abatacept, a selective T-cell costimulation modulator approved to treat JIA in children aged 6 years and older, and adalimumab, a tumor necrosis factor (TNF) blocker approved for treating JIA in children aged 4-17 years.

Abatacept, administered intravenously, is marketed as Orencia by Bristol-Myers Squibb Co. The company is conducting a 10-year pediatric safety study and is required by the FDA to establish a registry of 500 JIA patients who are treated with abatacept. The patients will be monitored for malignancies, other autoimmune diseases, and serious infections for 3 years. Between December 2005 and July 2009, there were seven reports of adverse events in children aged 7-16 years who were treated with abatacept, including one case of multiple sclerosis in a 14-year-old and lymphoma in a 16-year-old, which are listed in the label.

Adalimumab, administered subcutaneously, is marketed as Humira by Abbott Laboratories. Postmarketing requirements include conducting a 10-year safety study of the drug in 800 JIA patients aged 4-17 years.

In pediatric patients treated for at least 3 years, adverse events were similar in frequency and type to those reported in adults. But rates of hypersensitivity reactions and development of antibodies to adalimumab were higher among pediatric patients.

In August, the FDA reported an ongoing safety review, which suggested that pediatric patients who were treated with TNF blockers were at increased risk for lymphomas and other malignancies, including types rarely seen in children. A statement on this risk was added to the labels of all TNF blockers.

Since approval, 109 serious adverse events were reported in pediatric patients who were treated with adalimumab, of which 37 were cases of exposure in utero. There were two malignancies (lymphomas reported in a 16-year-old and a 10-year-old). Both patients had been on long-term treatment with other immunosuppressants, including other products associated with an increased malignancy risk.

Warnings about the potential risk of hepatotoxicity associated with the use of diclofenac have been added to the labels of all products containing the nonsteroidal anti-inflammatory drug, the Food and Drug Administration announced.

A notice on the FDA's MedWatch site said that the manufacturers—Endo Pharmaceuticals Inc. and Novartis Consumer Health Inc.—had revised the “hepatic effects” section of the diclofenac topical gel label to include new warnings and precautions about the potential for elevated liver function tests during treatment with diclofenac products, including the formulation marketed as Voltaren Gel 1%.

There have been postmarketing reports of severe hepatic reactions including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure in patients treated with diclofenac, according to the FDA. Some cases have been fatal or have resulted in liver transplantation.

Because severe hepatoxicity may be asymptomatic, the FDA and the revised label both recommend that clinicians periodically measure transaminase levels in patients taking diclofenac long term. Levels should be monitored within 4-8 weeks after initiating treatment, according to the FDA notice.

The labeling changes are summarized in a Dear Health Care Professional letter issued by the manufacturers.

For more information, call 800-452-0051. The MedWatch notice and letter can be viewed at www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm193047.htm

Warnings about the potential risk of hepatotoxicity associated with the use of diclofenac have been added to the labels of all products containing the nonsteroidal anti-inflammatory drug, the Food and Drug Administration announced.

A notice on the FDA's MedWatch site said that the manufacturers—Endo Pharmaceuticals Inc. and Novartis Consumer Health Inc.—had revised the “hepatic effects” section of the diclofenac topical gel label to include new warnings and precautions about the potential for elevated liver function tests during treatment with diclofenac products, including the formulation marketed as Voltaren Gel 1%.

There have been postmarketing reports of severe hepatic reactions including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure in patients treated with diclofenac, according to the FDA. Some cases have been fatal or have resulted in liver transplantation.

Because severe hepatoxicity may be asymptomatic, the FDA and the revised label both recommend that clinicians periodically measure transaminase levels in patients taking diclofenac long term. Levels should be monitored within 4-8 weeks after initiating treatment, according to the FDA notice.

The labeling changes are summarized in a Dear Health Care Professional letter issued by the manufacturers.

For more information, call 800-452-0051. The MedWatch notice and letter can be viewed at www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm193047.htm

Warnings about the potential risk of hepatotoxicity associated with the use of diclofenac have been added to the labels of all products containing the nonsteroidal anti-inflammatory drug, the Food and Drug Administration announced.

A notice on the FDA's MedWatch site said that the manufacturers—Endo Pharmaceuticals Inc. and Novartis Consumer Health Inc.—had revised the “hepatic effects” section of the diclofenac topical gel label to include new warnings and precautions about the potential for elevated liver function tests during treatment with diclofenac products, including the formulation marketed as Voltaren Gel 1%.

There have been postmarketing reports of severe hepatic reactions including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure in patients treated with diclofenac, according to the FDA. Some cases have been fatal or have resulted in liver transplantation.

Because severe hepatoxicity may be asymptomatic, the FDA and the revised label both recommend that clinicians periodically measure transaminase levels in patients taking diclofenac long term. Levels should be monitored within 4-8 weeks after initiating treatment, according to the FDA notice.

The labeling changes are summarized in a Dear Health Care Professional letter issued by the manufacturers.

For more information, call 800-452-0051. The MedWatch notice and letter can be viewed at www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm193047.htm

GAITHERSBURG, MD. — Studies of an inhaled formulation of the monobactam antibiotic aztreonam in patients with cystic fibrosis show that it is a safe and effective treatment for Pseudomonas aeruginosa lung infections in this population, most of a federal advisory panel agreed.

The Food and Drug Administration's Anti-Infective Drugs Advisory Committee voted 15-2 that the manufacturer, Gilead Sciences Inc., had provided substantial evidence that inhaled aztreonam, administered at a dose of 75 mg three times a day for 28 days, was safe and effective for the proposed indication: the improvement of respiratory symptoms and pulmonary function in patients who have cystic fibrosis (CF) with P. aeruginosa.

If aztreonam lysine for inhalation (AZLI) is approved, the company plans to market it as Cayston, with a novel, portable handheld nebulizer that delivers the 75-mg dose in 2–3 minutes. The panel was not asked to specifically vote on whether to recommend approval.

Inhaled aztreonam has already been approved for this indication in the European Union, Canada, and other countries. The intravenous formulation was approved in 1986 in the United States for indications that include P. aeruginosa infections, but not specifically for CF patients.

Although the FDA raised issues about whether 75 mg three times a day was the best dose, the panel unanimously agreed in a 17-0 vote that this dose had been shown to be safe and effective, although several panelists said that other doses should be studied.

AZLI was compared with placebo in two pivotal placebo-controlled phase III studies of patients aged 6 years and older with CF (mean age was in the mid-20s to early-30s), who had P. aeruginosa and forced expiratory volume in 1 second (FEV₁) of 25%–75% (predicted).

In one study, approximately 200 patients received 75 mg of AZLI or placebo twice or three times a day for 28 days, after completing 28 days of treatment with tobramycin inhalation solution (TOBI), the only FDA-approved inhaled antibiotic approved for treating P. aeruginosa in CF patients (approved in 1997). The primary end point—the time to need for inhaled or intravenous antipseudomonal antibiotics from the time they started AZLI or placebo—was a median of 92 days among those on AZLI, compared with a median of 71 days among those on placebo, a significant difference. Those on AZLI also had improvements in FEV₁, a secondary end point; these improvements were significantly greater than they were in those on placebo.

In a second study, which enrolled 164 patients treated with AZLI or placebo three times a day for 28 days, the primary end point was the change from day 0 to 28 in clinical symptoms, as assessed by the respiratory scores of a CF symptom questionnaire. In both studies, AZLI-treated patients also had significantly better mean changes in FEV₁ over a period of 28 days, a secondary end point, when compared with those on placebo.

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

GAITHERSBURG, MD. — Studies of an inhaled formulation of the monobactam antibiotic aztreonam in patients with cystic fibrosis show that it is a safe and effective treatment for Pseudomonas aeruginosa lung infections in this population, most of a federal advisory panel agreed.

The Food and Drug Administration's Anti-Infective Drugs Advisory Committee voted 15-2 that the manufacturer, Gilead Sciences Inc., had provided substantial evidence that inhaled aztreonam, administered at a dose of 75 mg three times a day for 28 days, was safe and effective for the proposed indication: the improvement of respiratory symptoms and pulmonary function in patients who have cystic fibrosis (CF) with P. aeruginosa.

If aztreonam lysine for inhalation (AZLI) is approved, the company plans to market it as Cayston, with a novel, portable handheld nebulizer that delivers the 75-mg dose in 2–3 minutes. The panel was not asked to specifically vote on whether to recommend approval.

Inhaled aztreonam has already been approved for this indication in the European Union, Canada, and other countries. The intravenous formulation was approved in 1986 in the United States for indications that include P. aeruginosa infections, but not specifically for CF patients.

Although the FDA raised issues about whether 75 mg three times a day was the best dose, the panel unanimously agreed in a 17-0 vote that this dose had been shown to be safe and effective, although several panelists said that other doses should be studied.

AZLI was compared with placebo in two pivotal placebo-controlled phase III studies of patients aged 6 years and older with CF (mean age was in the mid-20s to early-30s), who had P. aeruginosa and forced expiratory volume in 1 second (FEV₁) of 25%–75% (predicted).

In one study, approximately 200 patients received 75 mg of AZLI or placebo twice or three times a day for 28 days, after completing 28 days of treatment with tobramycin inhalation solution (TOBI), the only FDA-approved inhaled antibiotic approved for treating P. aeruginosa in CF patients (approved in 1997). The primary end point—the time to need for inhaled or intravenous antipseudomonal antibiotics from the time they started AZLI or placebo—was a median of 92 days among those on AZLI, compared with a median of 71 days among those on placebo, a significant difference. Those on AZLI also had improvements in FEV₁, a secondary end point; these improvements were significantly greater than they were in those on placebo.

In a second study, which enrolled 164 patients treated with AZLI or placebo three times a day for 28 days, the primary end point was the change from day 0 to 28 in clinical symptoms, as assessed by the respiratory scores of a CF symptom questionnaire. In both studies, AZLI-treated patients also had significantly better mean changes in FEV₁ over a period of 28 days, a secondary end point, when compared with those on placebo.

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

GAITHERSBURG, MD. — Studies of an inhaled formulation of the monobactam antibiotic aztreonam in patients with cystic fibrosis show that it is a safe and effective treatment for Pseudomonas aeruginosa lung infections in this population, most of a federal advisory panel agreed.

The Food and Drug Administration's Anti-Infective Drugs Advisory Committee voted 15-2 that the manufacturer, Gilead Sciences Inc., had provided substantial evidence that inhaled aztreonam, administered at a dose of 75 mg three times a day for 28 days, was safe and effective for the proposed indication: the improvement of respiratory symptoms and pulmonary function in patients who have cystic fibrosis (CF) with P. aeruginosa.

If aztreonam lysine for inhalation (AZLI) is approved, the company plans to market it as Cayston, with a novel, portable handheld nebulizer that delivers the 75-mg dose in 2–3 minutes. The panel was not asked to specifically vote on whether to recommend approval.

Inhaled aztreonam has already been approved for this indication in the European Union, Canada, and other countries. The intravenous formulation was approved in 1986 in the United States for indications that include P. aeruginosa infections, but not specifically for CF patients.

Although the FDA raised issues about whether 75 mg three times a day was the best dose, the panel unanimously agreed in a 17-0 vote that this dose had been shown to be safe and effective, although several panelists said that other doses should be studied.

AZLI was compared with placebo in two pivotal placebo-controlled phase III studies of patients aged 6 years and older with CF (mean age was in the mid-20s to early-30s), who had P. aeruginosa and forced expiratory volume in 1 second (FEV₁) of 25%–75% (predicted).

In one study, approximately 200 patients received 75 mg of AZLI or placebo twice or three times a day for 28 days, after completing 28 days of treatment with tobramycin inhalation solution (TOBI), the only FDA-approved inhaled antibiotic approved for treating P. aeruginosa in CF patients (approved in 1997). The primary end point—the time to need for inhaled or intravenous antipseudomonal antibiotics from the time they started AZLI or placebo—was a median of 92 days among those on AZLI, compared with a median of 71 days among those on placebo, a significant difference. Those on AZLI also had improvements in FEV₁, a secondary end point; these improvements were significantly greater than they were in those on placebo.

In a second study, which enrolled 164 patients treated with AZLI or placebo three times a day for 28 days, the primary end point was the change from day 0 to 28 in clinical symptoms, as assessed by the respiratory scores of a CF symptom questionnaire. In both studies, AZLI-treated patients also had significantly better mean changes in FEV₁ over a period of 28 days, a secondary end point, when compared with those on placebo.

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

COLLEGE PARK, MD. — Special training in safe prescription of long-acting opioid drugs, as well as the use of patient-prescriber agreements, could be required to earn federal approval to prescribe such products, under proposals discussed by an industry working group.

The working group presented those and other options at a public meeting held by the Food and Drug Administration. The meeting was part of an initiative to develop a class-wide risk evaluation and mitigation strategy (REMS) for long-acting opioid drugs.

The FDA last February informed manufacturers of long-acting opioid products that they would have to develop a single REMS for the drug class. The FDA wants to reduce the potential for abuse, misuse, overdose, and addiction associated with the use of the products and to ensure that their benefits outweigh their risks.

Under one element of the plan being-considered, clinicians seeking Drug Enforcement Agency registration to prescribe schedule II controlled substances would be required to certify that they were trained to safely prescribe and choose the appropriate patients for the drugs. Currently, there is no training requirement for a physician to obtain DEA registration. Giving the DEA such authority would require an act of Congress, according to one of the industry working group representatives.

While efforts to pass such legislation are underway, the working group members noted, voluntary programs could be developed, possibly with medical specialty societies.

Requiring such training raises the concern that some physicians would opt out of training—thus reducing access to the drugs for patients who need them, said Dr. John Jenkins, director of the Office of New Drugs, in the FDA's Center for Drug Evaluation and Research.

The REMS program's goals are to ensure that the drugs' risks don't exceed their benefits, while ensuring access for patients who need them, Dr. Jenkins noted during a press briefing after the meeting.

The drugs to be included in the REMS are brand name and generic products that contain fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Among the problems associated with those products include their use in patients who are non–opioid tolerant or otherwise inappropriately selected, as well as the drugs' misuse and abuse.

Dr. Jenkins cited the example of pain treatment with methadone—which, when taken too frequently, can result rapidly in an overdose.

Short-acting opioid products are not included in the discussion. But meeting participants expressed concern that an effective REMS for the long-acting products could shift misuse and abuse to the shorter-acting agents.

Other ideas proposed by the industry working group for the REMS include:

▸ A patient-prescriber agreement, which would serve as a tool to facilitate a discussion between physicians and patients.

▸ A medication information sheet.

▸ Metrics to assess the impact of the REMS. There should be a measure to determine whether the REMS impedes patients' access to appropriate medication, the working group noted.

The industry working group made no definitive conclusions at the meeting, however, and it has not developed a final plan for the REMS.

Dr. Jenkins said he couldn't predict when the REMS would be finalized. But an FDA advisory panel will meet in the spring to discuss the elements of the proposed REMS, to solicit advice from experts, and to hear public comment, he added. Until a final REMS is approved, Dr. Jenkins said, the FDA will require an interim REMS for any other products in the drug class.

Some physicians would opt out of training, thus reducing access to the drugs for patients who need them.

Source DR. JENKINSNCT00264810

COLLEGE PARK, MD. — Special training in safe prescription of long-acting opioid drugs, as well as the use of patient-prescriber agreements, could be required to earn federal approval to prescribe such products, under proposals discussed by an industry working group.

The working group presented those and other options at a public meeting held by the Food and Drug Administration. The meeting was part of an initiative to develop a class-wide risk evaluation and mitigation strategy (REMS) for long-acting opioid drugs.

The FDA last February informed manufacturers of long-acting opioid products that they would have to develop a single REMS for the drug class. The FDA wants to reduce the potential for abuse, misuse, overdose, and addiction associated with the use of the products and to ensure that their benefits outweigh their risks.

Under one element of the plan being-considered, clinicians seeking Drug Enforcement Agency registration to prescribe schedule II controlled substances would be required to certify that they were trained to safely prescribe and choose the appropriate patients for the drugs. Currently, there is no training requirement for a physician to obtain DEA registration. Giving the DEA such authority would require an act of Congress, according to one of the industry working group representatives.

While efforts to pass such legislation are underway, the working group members noted, voluntary programs could be developed, possibly with medical specialty societies.

Requiring such training raises the concern that some physicians would opt out of training—thus reducing access to the drugs for patients who need them, said Dr. John Jenkins, director of the Office of New Drugs, in the FDA's Center for Drug Evaluation and Research.

The REMS program's goals are to ensure that the drugs' risks don't exceed their benefits, while ensuring access for patients who need them, Dr. Jenkins noted during a press briefing after the meeting.

The drugs to be included in the REMS are brand name and generic products that contain fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Among the problems associated with those products include their use in patients who are non–opioid tolerant or otherwise inappropriately selected, as well as the drugs' misuse and abuse.

Dr. Jenkins cited the example of pain treatment with methadone—which, when taken too frequently, can result rapidly in an overdose.

Short-acting opioid products are not included in the discussion. But meeting participants expressed concern that an effective REMS for the long-acting products could shift misuse and abuse to the shorter-acting agents.

Other ideas proposed by the industry working group for the REMS include:

▸ A patient-prescriber agreement, which would serve as a tool to facilitate a discussion between physicians and patients.

▸ A medication information sheet.

▸ Metrics to assess the impact of the REMS. There should be a measure to determine whether the REMS impedes patients' access to appropriate medication, the working group noted.

The industry working group made no definitive conclusions at the meeting, however, and it has not developed a final plan for the REMS.

Dr. Jenkins said he couldn't predict when the REMS would be finalized. But an FDA advisory panel will meet in the spring to discuss the elements of the proposed REMS, to solicit advice from experts, and to hear public comment, he added. Until a final REMS is approved, Dr. Jenkins said, the FDA will require an interim REMS for any other products in the drug class.

Some physicians would opt out of training, thus reducing access to the drugs for patients who need them.

Source DR. JENKINSNCT00264810

COLLEGE PARK, MD. — Special training in safe prescription of long-acting opioid drugs, as well as the use of patient-prescriber agreements, could be required to earn federal approval to prescribe such products, under proposals discussed by an industry working group.

The working group presented those and other options at a public meeting held by the Food and Drug Administration. The meeting was part of an initiative to develop a class-wide risk evaluation and mitigation strategy (REMS) for long-acting opioid drugs.

The FDA last February informed manufacturers of long-acting opioid products that they would have to develop a single REMS for the drug class. The FDA wants to reduce the potential for abuse, misuse, overdose, and addiction associated with the use of the products and to ensure that their benefits outweigh their risks.

Under one element of the plan being-considered, clinicians seeking Drug Enforcement Agency registration to prescribe schedule II controlled substances would be required to certify that they were trained to safely prescribe and choose the appropriate patients for the drugs. Currently, there is no training requirement for a physician to obtain DEA registration. Giving the DEA such authority would require an act of Congress, according to one of the industry working group representatives.

While efforts to pass such legislation are underway, the working group members noted, voluntary programs could be developed, possibly with medical specialty societies.

Requiring such training raises the concern that some physicians would opt out of training—thus reducing access to the drugs for patients who need them, said Dr. John Jenkins, director of the Office of New Drugs, in the FDA's Center for Drug Evaluation and Research.

The REMS program's goals are to ensure that the drugs' risks don't exceed their benefits, while ensuring access for patients who need them, Dr. Jenkins noted during a press briefing after the meeting.

The drugs to be included in the REMS are brand name and generic products that contain fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Among the problems associated with those products include their use in patients who are non–opioid tolerant or otherwise inappropriately selected, as well as the drugs' misuse and abuse.

Dr. Jenkins cited the example of pain treatment with methadone—which, when taken too frequently, can result rapidly in an overdose.

Short-acting opioid products are not included in the discussion. But meeting participants expressed concern that an effective REMS for the long-acting products could shift misuse and abuse to the shorter-acting agents.

Other ideas proposed by the industry working group for the REMS include:

▸ A patient-prescriber agreement, which would serve as a tool to facilitate a discussion between physicians and patients.

▸ A medication information sheet.

▸ Metrics to assess the impact of the REMS. There should be a measure to determine whether the REMS impedes patients' access to appropriate medication, the working group noted.

The industry working group made no definitive conclusions at the meeting, however, and it has not developed a final plan for the REMS.

Dr. Jenkins said he couldn't predict when the REMS would be finalized. But an FDA advisory panel will meet in the spring to discuss the elements of the proposed REMS, to solicit advice from experts, and to hear public comment, he added. Until a final REMS is approved, Dr. Jenkins said, the FDA will require an interim REMS for any other products in the drug class.

Some physicians would opt out of training, thus reducing access to the drugs for patients who need them.

Source DR. JENKINSNCT00264810

Warnings related to the risk of sudden death and cardiac dysrhythmias associated with desipramine have been added to the label of the tricyclic antidepressant, according to the Food and Drug Administration.

A notice posted on the FDA's MedWatch site states that “extreme caution” should be used when desipramine is prescribed to patients who have a family history of sudden death, cardiac dysrhythmias, and cardiac conduction disturbances. This statement has been added to the general warnings section of the label. Also added to this section is the statement that “seizures precede cardiac dysrhythmias and death in some patients.”

Desipramine, approved in 1964, is marketed as Norpramin by Sanofi-Aventis, which issued a Dear Healthcare Professional letter summarizing the changes to the label.

The letter lists other related changes to the overdosage section of the label, including the statement that desipramine overdoses have resulted in a higher death rate when compared to overdoses of other tricyclics. The letter also contains descriptions of early EKG changes associated with overdoses, and the recommendation to administer activated charcoal for patients who present early after an overdose. This section also now states that “serum alkalinization with intravenous sodium bicarbonate and hyperventilation [as needed] should be instituted in patients manifesting significant toxicity such as QRS widening,” and that “dysrhythmias despite adequate alkalemia may respond to overdrive pacing, beta-agonist infusions, and magnesium therapy.”

Warnings related to the risk of sudden death and cardiac dysrhythmias associated with desipramine have been added to the label of the tricyclic antidepressant, according to the Food and Drug Administration.

A notice posted on the FDA's MedWatch site states that “extreme caution” should be used when desipramine is prescribed to patients who have a family history of sudden death, cardiac dysrhythmias, and cardiac conduction disturbances. This statement has been added to the general warnings section of the label. Also added to this section is the statement that “seizures precede cardiac dysrhythmias and death in some patients.”

Desipramine, approved in 1964, is marketed as Norpramin by Sanofi-Aventis, which issued a Dear Healthcare Professional letter summarizing the changes to the label.

The letter lists other related changes to the overdosage section of the label, including the statement that desipramine overdoses have resulted in a higher death rate when compared to overdoses of other tricyclics. The letter also contains descriptions of early EKG changes associated with overdoses, and the recommendation to administer activated charcoal for patients who present early after an overdose. This section also now states that “serum alkalinization with intravenous sodium bicarbonate and hyperventilation [as needed] should be instituted in patients manifesting significant toxicity such as QRS widening,” and that “dysrhythmias despite adequate alkalemia may respond to overdrive pacing, beta-agonist infusions, and magnesium therapy.”

Warnings related to the risk of sudden death and cardiac dysrhythmias associated with desipramine have been added to the label of the tricyclic antidepressant, according to the Food and Drug Administration.

A notice posted on the FDA's MedWatch site states that “extreme caution” should be used when desipramine is prescribed to patients who have a family history of sudden death, cardiac dysrhythmias, and cardiac conduction disturbances. This statement has been added to the general warnings section of the label. Also added to this section is the statement that “seizures precede cardiac dysrhythmias and death in some patients.”

Desipramine, approved in 1964, is marketed as Norpramin by Sanofi-Aventis, which issued a Dear Healthcare Professional letter summarizing the changes to the label.

The letter lists other related changes to the overdosage section of the label, including the statement that desipramine overdoses have resulted in a higher death rate when compared to overdoses of other tricyclics. The letter also contains descriptions of early EKG changes associated with overdoses, and the recommendation to administer activated charcoal for patients who present early after an overdose. This section also now states that “serum alkalinization with intravenous sodium bicarbonate and hyperventilation [as needed] should be instituted in patients manifesting significant toxicity such as QRS widening,” and that “dysrhythmias despite adequate alkalemia may respond to overdrive pacing, beta-agonist infusions, and magnesium therapy.”

GAITHERSBURG, MD. — A Food and Drug Administration advisory panel on voted 6–1 that a novel device that uses thermal energy to ablate smooth muscle in the airway during bronchoscopy could be approved under certain conditions, as a treatment for severe, persistent asthma in people aged 18 years and older.

At the meeting, members of the FDA's Anesthesiology and Respiratory Therapy Devices Panel agreed that there was reasonable evidence that the device was safe and effective for this indication, but stipulated several conditions for approval, reflecting concerns about the need for longer-term safety and efficacy data.

The conditions included requiring the manufacturer to enroll all patients treated with the device after approval in a registry, which would follow the durability of the therapeutic effects and safety; and not using the device in patients with impaired coagulation or in those who are on anticoagulant medication, because hemoptysis was reported in six treated patients in the pivotal study.

Other conditions for approval were that physicians who use the device be adequately trained, and that patients not be retreated with the device until clinical trial data on the effects of retreatment are available. The panel also unanimously recommended postmarketing studies to further evaluate the safety and effectiveness of the device, with end points that include emergency department visits for respiratory symptoms, corticosteroid requirements, asthma exacerbations, and hospitalizations.

Components of the Alair Bronchial Thermoplasty system include a radiofrequency (RF) generator and a single-use catheter with an electrode basket at the tip that delivers RF energy to surrounding tissue. Treatment results in clinical improvements in people with severe asthma by using thermal energy “to reduce the airway smooth muscle responsible for airway constriction in asthma patients,” according to the device's manufacturer, Asthmatx.

The pivotal study conducted in six countries compared treatment with the device in 190 patients to sham bronchoscopy in 98 patients (where the catheter was deployed, without RF). Patients, whose median age was 41 years, had severe persistent asthma that was “not well controlled” (30%) or “very poorly controlled” (70%), and required high doses of inhaled corticosteroids and long-acting beta agonist therapy. Treatment was administered during three separate outpatient bronchoscopies 3 weeks apart. Each procedure took about 30 minutes, according to Asthmatx.

The primary end point was the average of the changes in 6-, 9-, and 12-month Asthma Quality of Life Questionnaire (AQLQ) scores, a patient self-administered validated questionnaire, from baseline. Scores increased among patients in both groups, but the average of the three scores was 0.21 points greater among those in the active treatment group, compared with those in the sham group, which just missed statistical significance, according to the FDA's analysis. The largest effects of treatment were seen at U.S. study sites, but in Brazil, improvements in the scores were somewhat higher among those in the sham group, which panelists agreed was a concern. Some panelists thought this may have been due to the free maintenance medications received by all the patients enrolled at the Brazil sites, possibly reflecting greater compliance with medication therapy.

Some of the study's secondary end points, including rates of severe exacerbations after treatment; days lost from work, school, or other daily activities due to asthma symptoms; and emergency department visits for respiratory symptoms, were lower among those treated with the device. Nearly 79% of those on Alair had a change in the AQLQ score of at least 0.5 (which the company said is the threshold for a clinically meaningful change), compared with 64.3% of those on sham treatment, the company reported.

Respiratory-related events, including asthma symptoms, were higher among those in the device-treated patients during the treatment phase (from the time of the first bronchoscopy through 6 weeks after the third bronchoscopy) but lower than among those in the sham group after that time. A total of six patients (3%) treated with the device had hemoptysis, which typically occurred soon after the procedure and was self-limited; one patient developed severe hemoptysis 31 days after treatment. But there were no cases in sham-treated patients. There were no treatment-related deaths or withdrawals for worsening asthma in the study.

Although the primary effectiveness end point in the pivotal study was not met, panelists supporting approval said they considered some of the secondary end points to be clinically relevant.

The panel generally agreed that the device appeared to be safe, but that long-term safety should be monitored, including the potential for dysplastic changes and malignancy in the treated areas. (There has been no evidence of structural abnormalities or neoplasia during up to 5 years of follow-up, according to Asthmatx.)

Panelist Dr. Sharon Rounds, chief of pulmonary/critical care at Providence (R.I.) Veterans Affairs Medical Center, said that despite her concerns about the regional variability in the effectiveness results, she was impressed with the secondary end points and that “on balance, the risks are offset by the reasonably effective nature of the intervention.” A long-term study following patients for at least 5 years after treatment is needed to monitor treatment durability and potential long-term sequelae of “undoubted damage to the epithelium and other components of the airway wall, in addition to bronchial smooth muscle,” she added.

Another panel member, Dr. Polly Parsons, director of the pulmonary and critical care medicine unit at the University of Vermont, Burlington, agreed that the evidence provided “reasonable assurance” that the device was safe and effective, but added it would be a concern if it was used in patients “beyond those defined as eligible for the trial.”

The panelist who voted against approval, Dr. Sandra Willsie, a pulmonologist in Overland Park, Kan., said, “I believe there's promise here, but I have misgivings in view of the very impressive placebo effect that the data are robust enough.”

The FDA usually follows the recommendations of its advisory panels. If the agent is approved, the company plans further studies, including one that will follow patients in the pivotal trial through 5 years, and will provide didactic and interactive training for physicians.

GAITHERSBURG, MD. — A Food and Drug Administration advisory panel on voted 6–1 that a novel device that uses thermal energy to ablate smooth muscle in the airway during bronchoscopy could be approved under certain conditions, as a treatment for severe, persistent asthma in people aged 18 years and older.

At the meeting, members of the FDA's Anesthesiology and Respiratory Therapy Devices Panel agreed that there was reasonable evidence that the device was safe and effective for this indication, but stipulated several conditions for approval, reflecting concerns about the need for longer-term safety and efficacy data.

The conditions included requiring the manufacturer to enroll all patients treated with the device after approval in a registry, which would follow the durability of the therapeutic effects and safety; and not using the device in patients with impaired coagulation or in those who are on anticoagulant medication, because hemoptysis was reported in six treated patients in the pivotal study.

Other conditions for approval were that physicians who use the device be adequately trained, and that patients not be retreated with the device until clinical trial data on the effects of retreatment are available. The panel also unanimously recommended postmarketing studies to further evaluate the safety and effectiveness of the device, with end points that include emergency department visits for respiratory symptoms, corticosteroid requirements, asthma exacerbations, and hospitalizations.

Components of the Alair Bronchial Thermoplasty system include a radiofrequency (RF) generator and a single-use catheter with an electrode basket at the tip that delivers RF energy to surrounding tissue. Treatment results in clinical improvements in people with severe asthma by using thermal energy “to reduce the airway smooth muscle responsible for airway constriction in asthma patients,” according to the device's manufacturer, Asthmatx.

The pivotal study conducted in six countries compared treatment with the device in 190 patients to sham bronchoscopy in 98 patients (where the catheter was deployed, without RF). Patients, whose median age was 41 years, had severe persistent asthma that was “not well controlled” (30%) or “very poorly controlled” (70%), and required high doses of inhaled corticosteroids and long-acting beta agonist therapy. Treatment was administered during three separate outpatient bronchoscopies 3 weeks apart. Each procedure took about 30 minutes, according to Asthmatx.

The primary end point was the average of the changes in 6-, 9-, and 12-month Asthma Quality of Life Questionnaire (AQLQ) scores, a patient self-administered validated questionnaire, from baseline. Scores increased among patients in both groups, but the average of the three scores was 0.21 points greater among those in the active treatment group, compared with those in the sham group, which just missed statistical significance, according to the FDA's analysis. The largest effects of treatment were seen at U.S. study sites, but in Brazil, improvements in the scores were somewhat higher among those in the sham group, which panelists agreed was a concern. Some panelists thought this may have been due to the free maintenance medications received by all the patients enrolled at the Brazil sites, possibly reflecting greater compliance with medication therapy.

Some of the study's secondary end points, including rates of severe exacerbations after treatment; days lost from work, school, or other daily activities due to asthma symptoms; and emergency department visits for respiratory symptoms, were lower among those treated with the device. Nearly 79% of those on Alair had a change in the AQLQ score of at least 0.5 (which the company said is the threshold for a clinically meaningful change), compared with 64.3% of those on sham treatment, the company reported.

Respiratory-related events, including asthma symptoms, were higher among those in the device-treated patients during the treatment phase (from the time of the first bronchoscopy through 6 weeks after the third bronchoscopy) but lower than among those in the sham group after that time. A total of six patients (3%) treated with the device had hemoptysis, which typically occurred soon after the procedure and was self-limited; one patient developed severe hemoptysis 31 days after treatment. But there were no cases in sham-treated patients. There were no treatment-related deaths or withdrawals for worsening asthma in the study.

Although the primary effectiveness end point in the pivotal study was not met, panelists supporting approval said they considered some of the secondary end points to be clinically relevant.

The panel generally agreed that the device appeared to be safe, but that long-term safety should be monitored, including the potential for dysplastic changes and malignancy in the treated areas. (There has been no evidence of structural abnormalities or neoplasia during up to 5 years of follow-up, according to Asthmatx.)

Panelist Dr. Sharon Rounds, chief of pulmonary/critical care at Providence (R.I.) Veterans Affairs Medical Center, said that despite her concerns about the regional variability in the effectiveness results, she was impressed with the secondary end points and that “on balance, the risks are offset by the reasonably effective nature of the intervention.” A long-term study following patients for at least 5 years after treatment is needed to monitor treatment durability and potential long-term sequelae of “undoubted damage to the epithelium and other components of the airway wall, in addition to bronchial smooth muscle,” she added.

Another panel member, Dr. Polly Parsons, director of the pulmonary and critical care medicine unit at the University of Vermont, Burlington, agreed that the evidence provided “reasonable assurance” that the device was safe and effective, but added it would be a concern if it was used in patients “beyond those defined as eligible for the trial.”

The panelist who voted against approval, Dr. Sandra Willsie, a pulmonologist in Overland Park, Kan., said, “I believe there's promise here, but I have misgivings in view of the very impressive placebo effect that the data are robust enough.”

The FDA usually follows the recommendations of its advisory panels. If the agent is approved, the company plans further studies, including one that will follow patients in the pivotal trial through 5 years, and will provide didactic and interactive training for physicians.

GAITHERSBURG, MD. — A Food and Drug Administration advisory panel on voted 6–1 that a novel device that uses thermal energy to ablate smooth muscle in the airway during bronchoscopy could be approved under certain conditions, as a treatment for severe, persistent asthma in people aged 18 years and older.

At the meeting, members of the FDA's Anesthesiology and Respiratory Therapy Devices Panel agreed that there was reasonable evidence that the device was safe and effective for this indication, but stipulated several conditions for approval, reflecting concerns about the need for longer-term safety and efficacy data.

The conditions included requiring the manufacturer to enroll all patients treated with the device after approval in a registry, which would follow the durability of the therapeutic effects and safety; and not using the device in patients with impaired coagulation or in those who are on anticoagulant medication, because hemoptysis was reported in six treated patients in the pivotal study.

Other conditions for approval were that physicians who use the device be adequately trained, and that patients not be retreated with the device until clinical trial data on the effects of retreatment are available. The panel also unanimously recommended postmarketing studies to further evaluate the safety and effectiveness of the device, with end points that include emergency department visits for respiratory symptoms, corticosteroid requirements, asthma exacerbations, and hospitalizations.

Components of the Alair Bronchial Thermoplasty system include a radiofrequency (RF) generator and a single-use catheter with an electrode basket at the tip that delivers RF energy to surrounding tissue. Treatment results in clinical improvements in people with severe asthma by using thermal energy “to reduce the airway smooth muscle responsible for airway constriction in asthma patients,” according to the device's manufacturer, Asthmatx.

The pivotal study conducted in six countries compared treatment with the device in 190 patients to sham bronchoscopy in 98 patients (where the catheter was deployed, without RF). Patients, whose median age was 41 years, had severe persistent asthma that was “not well controlled” (30%) or “very poorly controlled” (70%), and required high doses of inhaled corticosteroids and long-acting beta agonist therapy. Treatment was administered during three separate outpatient bronchoscopies 3 weeks apart. Each procedure took about 30 minutes, according to Asthmatx.

The primary end point was the average of the changes in 6-, 9-, and 12-month Asthma Quality of Life Questionnaire (AQLQ) scores, a patient self-administered validated questionnaire, from baseline. Scores increased among patients in both groups, but the average of the three scores was 0.21 points greater among those in the active treatment group, compared with those in the sham group, which just missed statistical significance, according to the FDA's analysis. The largest effects of treatment were seen at U.S. study sites, but in Brazil, improvements in the scores were somewhat higher among those in the sham group, which panelists agreed was a concern. Some panelists thought this may have been due to the free maintenance medications received by all the patients enrolled at the Brazil sites, possibly reflecting greater compliance with medication therapy.

Some of the study's secondary end points, including rates of severe exacerbations after treatment; days lost from work, school, or other daily activities due to asthma symptoms; and emergency department visits for respiratory symptoms, were lower among those treated with the device. Nearly 79% of those on Alair had a change in the AQLQ score of at least 0.5 (which the company said is the threshold for a clinically meaningful change), compared with 64.3% of those on sham treatment, the company reported.

Respiratory-related events, including asthma symptoms, were higher among those in the device-treated patients during the treatment phase (from the time of the first bronchoscopy through 6 weeks after the third bronchoscopy) but lower than among those in the sham group after that time. A total of six patients (3%) treated with the device had hemoptysis, which typically occurred soon after the procedure and was self-limited; one patient developed severe hemoptysis 31 days after treatment. But there were no cases in sham-treated patients. There were no treatment-related deaths or withdrawals for worsening asthma in the study.

Although the primary effectiveness end point in the pivotal study was not met, panelists supporting approval said they considered some of the secondary end points to be clinically relevant.

The panel generally agreed that the device appeared to be safe, but that long-term safety should be monitored, including the potential for dysplastic changes and malignancy in the treated areas. (There has been no evidence of structural abnormalities or neoplasia during up to 5 years of follow-up, according to Asthmatx.)

Panelist Dr. Sharon Rounds, chief of pulmonary/critical care at Providence (R.I.) Veterans Affairs Medical Center, said that despite her concerns about the regional variability in the effectiveness results, she was impressed with the secondary end points and that “on balance, the risks are offset by the reasonably effective nature of the intervention.” A long-term study following patients for at least 5 years after treatment is needed to monitor treatment durability and potential long-term sequelae of “undoubted damage to the epithelium and other components of the airway wall, in addition to bronchial smooth muscle,” she added.

Another panel member, Dr. Polly Parsons, director of the pulmonary and critical care medicine unit at the University of Vermont, Burlington, agreed that the evidence provided “reasonable assurance” that the device was safe and effective, but added it would be a concern if it was used in patients “beyond those defined as eligible for the trial.”

The panelist who voted against approval, Dr. Sandra Willsie, a pulmonologist in Overland Park, Kan., said, “I believe there's promise here, but I have misgivings in view of the very impressive placebo effect that the data are robust enough.”

The FDA usually follows the recommendations of its advisory panels. If the agent is approved, the company plans further studies, including one that will follow patients in the pivotal trial through 5 years, and will provide didactic and interactive training for physicians.

SILVER SPRING, MD. — Reducing preventable injuries from medication errors, misuse, and abuse is the goal of an initiative being launched by the Food and Drug Administration, agency officials announced at a briefing.

The Safe Use Initiative is intended to “reduce preventable harm by identifying specific, preventable medication risks and developing, implementing, and evaluating cross-sector interventions with partners who are committed to safe medication use,” FDA officials said. In addition to health care professionals, partners will include federal agencies, professional societies, pharmacies, hospitals, and manufacturers, as well as patients, caregivers, and consumers.

Drugs, drug classes, and therapeutic situations associated with preventable harm will be identified as part of the initiative.

In addition, the initiative will use measures of success to evaluate the impact of those interventions, Dr. Margaret Hamburg, FDA Commissioner, said during the briefing. Each year, adverse events from drug use result in more than 4 million visits to emergency rooms, physicians' offices, and outpatient facilities, and 117,000 hospitalizations, she said.

As many as half of all medication injuries—which include dosing errors, mixups during drug administration, and unintentional misuse of the medication—could be prevented with currently available information about the medication, Dr. Hamburg added.

During the briefing, Dr. Janet Woodcock, who will be spear-heading the initiative, distinguished between the events targeted by the initiative and inherent medication risks that are not preventable, such as side effects of chemotherapy. Most preventable injuries are caused by a lack of knowledge about the medication, including by prescribers and patients at the point of care, said Dr. Woodcock, director of the FDA's Center for Drug Evaluation and Research.

Dr. Woodcock said that the agency has discussed the initiative with physicians' and nurses' professional groups, and will seek input from the health care community and the public to determine what they perceive to be the biggest problems. Proposed interventions will be specific to a particular problem, she said. For example, measures could be taken to reduce the number of operating room fires (currently about 600 a year), the risks of inadvertent overexposure to acetaminophen, and contamination from multiple-use medication vials.

Dr. Woodcock and Dr. Hamburg cited the following estimates during the briefing:

▸ The Institute of Medicine estimated that every year 400,000 hospitalized patients have a preventable injury.

▸ The cost of preventable injuries from medications exceeds $4 billion annually, according to the IOM.

▸ An estimated 600,000 emergency department visits per year are caused by unsupervised ingestion of medications among children under age 12.

The agency also announced a new draft guidance document on delivery devices for over-the-counter liquid drug products for companies that manufacture, market, or distribute medications such as elixirs, suspensions, and syrups, which are packaged with calibrated cups, droppers, syringes, or other dosage delivery devices.

The draft guidance addresses “ongoing safety concerns about the serious potential for accidental drug overdoses of OTC liquid drug products that can result from the use of dosage delivery devices with markings that are inconsistent or incompatible with the labeled dosage directions for OTC drug products,” according to the document published in the Federal Register on Nov. 4.

For information on the safety initiative, visit www.fda.gov/Drugs/DrugSafety/ucm187806.htmwww.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM188992.pdf

SILVER SPRING, MD. — Reducing preventable injuries from medication errors, misuse, and abuse is the goal of an initiative being launched by the Food and Drug Administration, agency officials announced at a briefing.

The Safe Use Initiative is intended to “reduce preventable harm by identifying specific, preventable medication risks and developing, implementing, and evaluating cross-sector interventions with partners who are committed to safe medication use,” FDA officials said. In addition to health care professionals, partners will include federal agencies, professional societies, pharmacies, hospitals, and manufacturers, as well as patients, caregivers, and consumers.

Drugs, drug classes, and therapeutic situations associated with preventable harm will be identified as part of the initiative.

In addition, the initiative will use measures of success to evaluate the impact of those interventions, Dr. Margaret Hamburg, FDA Commissioner, said during the briefing. Each year, adverse events from drug use result in more than 4 million visits to emergency rooms, physicians' offices, and outpatient facilities, and 117,000 hospitalizations, she said.

As many as half of all medication injuries—which include dosing errors, mixups during drug administration, and unintentional misuse of the medication—could be prevented with currently available information about the medication, Dr. Hamburg added.

During the briefing, Dr. Janet Woodcock, who will be spear-heading the initiative, distinguished between the events targeted by the initiative and inherent medication risks that are not preventable, such as side effects of chemotherapy. Most preventable injuries are caused by a lack of knowledge about the medication, including by prescribers and patients at the point of care, said Dr. Woodcock, director of the FDA's Center for Drug Evaluation and Research.

Dr. Woodcock said that the agency has discussed the initiative with physicians' and nurses' professional groups, and will seek input from the health care community and the public to determine what they perceive to be the biggest problems. Proposed interventions will be specific to a particular problem, she said. For example, measures could be taken to reduce the number of operating room fires (currently about 600 a year), the risks of inadvertent overexposure to acetaminophen, and contamination from multiple-use medication vials.

Dr. Woodcock and Dr. Hamburg cited the following estimates during the briefing:

▸ The Institute of Medicine estimated that every year 400,000 hospitalized patients have a preventable injury.

▸ The cost of preventable injuries from medications exceeds $4 billion annually, according to the IOM.

▸ An estimated 600,000 emergency department visits per year are caused by unsupervised ingestion of medications among children under age 12.

The agency also announced a new draft guidance document on delivery devices for over-the-counter liquid drug products for companies that manufacture, market, or distribute medications such as elixirs, suspensions, and syrups, which are packaged with calibrated cups, droppers, syringes, or other dosage delivery devices.

The draft guidance addresses “ongoing safety concerns about the serious potential for accidental drug overdoses of OTC liquid drug products that can result from the use of dosage delivery devices with markings that are inconsistent or incompatible with the labeled dosage directions for OTC drug products,” according to the document published in the Federal Register on Nov. 4.

For information on the safety initiative, visit www.fda.gov/Drugs/DrugSafety/ucm187806.htmwww.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM188992.pdf

SILVER SPRING, MD. — Reducing preventable injuries from medication errors, misuse, and abuse is the goal of an initiative being launched by the Food and Drug Administration, agency officials announced at a briefing.

The Safe Use Initiative is intended to “reduce preventable harm by identifying specific, preventable medication risks and developing, implementing, and evaluating cross-sector interventions with partners who are committed to safe medication use,” FDA officials said. In addition to health care professionals, partners will include federal agencies, professional societies, pharmacies, hospitals, and manufacturers, as well as patients, caregivers, and consumers.

Drugs, drug classes, and therapeutic situations associated with preventable harm will be identified as part of the initiative.

In addition, the initiative will use measures of success to evaluate the impact of those interventions, Dr. Margaret Hamburg, FDA Commissioner, said during the briefing. Each year, adverse events from drug use result in more than 4 million visits to emergency rooms, physicians' offices, and outpatient facilities, and 117,000 hospitalizations, she said.

As many as half of all medication injuries—which include dosing errors, mixups during drug administration, and unintentional misuse of the medication—could be prevented with currently available information about the medication, Dr. Hamburg added.

During the briefing, Dr. Janet Woodcock, who will be spear-heading the initiative, distinguished between the events targeted by the initiative and inherent medication risks that are not preventable, such as side effects of chemotherapy. Most preventable injuries are caused by a lack of knowledge about the medication, including by prescribers and patients at the point of care, said Dr. Woodcock, director of the FDA's Center for Drug Evaluation and Research.

Dr. Woodcock said that the agency has discussed the initiative with physicians' and nurses' professional groups, and will seek input from the health care community and the public to determine what they perceive to be the biggest problems. Proposed interventions will be specific to a particular problem, she said. For example, measures could be taken to reduce the number of operating room fires (currently about 600 a year), the risks of inadvertent overexposure to acetaminophen, and contamination from multiple-use medication vials.

Dr. Woodcock and Dr. Hamburg cited the following estimates during the briefing:

▸ The Institute of Medicine estimated that every year 400,000 hospitalized patients have a preventable injury.

▸ The cost of preventable injuries from medications exceeds $4 billion annually, according to the IOM.

▸ An estimated 600,000 emergency department visits per year are caused by unsupervised ingestion of medications among children under age 12.

The agency also announced a new draft guidance document on delivery devices for over-the-counter liquid drug products for companies that manufacture, market, or distribute medications such as elixirs, suspensions, and syrups, which are packaged with calibrated cups, droppers, syringes, or other dosage delivery devices.

The draft guidance addresses “ongoing safety concerns about the serious potential for accidental drug overdoses of OTC liquid drug products that can result from the use of dosage delivery devices with markings that are inconsistent or incompatible with the labeled dosage directions for OTC drug products,” according to the document published in the Federal Register on Nov. 4.

For information on the safety initiative, visit www.fda.gov/Drugs/DrugSafety/ucm187806.htmwww.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM188992.pdf

Type 2 diabetes patients had a greater likelihood of having an acute myocardial infarction if they were treated with human neutral protamine hagedorn (NPH) insulin than if they were treated with insulin glargine, according to findings from a large retrospective study published online in the American Journal of Cardiology.

The results should be interpreted cautiously, noted the study's lead author Dr. George G. Rhoads, of the University of Medicine and Dentistry of New Jersey School of Public Health in Piscataway, and his associates.

However, they do “raise the possibility that specific insulin formulations or regimens might confer different levels of risk of [acute myocardial infarction] in patients with type 2 diabetes mellitus, and that this effect might be independent of the intensity of glucose control,” they wrote (Am. J. Cardiol. 2009;104:910-6).

The investigators culled data from the Integrated Health Care Information System, a large administrative database involving enrollees of more than 30 U.S. managed health care plans.

All the inpatient claims analyzed were for acute MIs among patients who were taking oral antidiabetic agents after initiation of either NPH, a basal insulin (5,461 patients), or insulin glargine, a newer, long-acting synthetic insulin analogue (14,730 patients). Their mean age was 56 years.

In the NPH group, significantly more patients were women and the rates of baseline comorbidities, medical claims for hypoglycemia, and medical service use for diabetes were higher, but the rates of hypertension, hyperlipidemia, and statin use were lower. The average adjusted hemoglobin A_1c was about 8% in the two groups.

During a mean 2-year follow-up period after initiating insulin treatment, the risk of an acute MI was 56% greater in the NPH group than in the glargine group.

Among the possible mechanisms that might help explain the difference was a higher rate of hypoglycemic events, according to the investigators; however, after adjustment for such events, the association did not change significantly.

There is a paucity of information on the cardiovascular safety of injectable insulin agents; and the long-term safety of NPH insulin has not been compared with that of the newer synthetic insulins.

The study was sponsored by Sanofi-Aventis, the manufacturer of insulin glargine. Dr. Rhoads has served as a consultant to Sanofi-Aventis; other authors have served as speaker, adviser, and consultant for the company.

Type 2 diabetes patients had a greater likelihood of having an acute myocardial infarction if they were treated with human neutral protamine hagedorn (NPH) insulin than if they were treated with insulin glargine, according to findings from a large retrospective study published online in the American Journal of Cardiology.

The results should be interpreted cautiously, noted the study's lead author Dr. George G. Rhoads, of the University of Medicine and Dentistry of New Jersey School of Public Health in Piscataway, and his associates.

However, they do “raise the possibility that specific insulin formulations or regimens might confer different levels of risk of [acute myocardial infarction] in patients with type 2 diabetes mellitus, and that this effect might be independent of the intensity of glucose control,” they wrote (Am. J. Cardiol. 2009;104:910-6).

The investigators culled data from the Integrated Health Care Information System, a large administrative database involving enrollees of more than 30 U.S. managed health care plans.

All the inpatient claims analyzed were for acute MIs among patients who were taking oral antidiabetic agents after initiation of either NPH, a basal insulin (5,461 patients), or insulin glargine, a newer, long-acting synthetic insulin analogue (14,730 patients). Their mean age was 56 years.

In the NPH group, significantly more patients were women and the rates of baseline comorbidities, medical claims for hypoglycemia, and medical service use for diabetes were higher, but the rates of hypertension, hyperlipidemia, and statin use were lower. The average adjusted hemoglobin A_1c was about 8% in the two groups.

During a mean 2-year follow-up period after initiating insulin treatment, the risk of an acute MI was 56% greater in the NPH group than in the glargine group.

Among the possible mechanisms that might help explain the difference was a higher rate of hypoglycemic events, according to the investigators; however, after adjustment for such events, the association did not change significantly.

There is a paucity of information on the cardiovascular safety of injectable insulin agents; and the long-term safety of NPH insulin has not been compared with that of the newer synthetic insulins.

The study was sponsored by Sanofi-Aventis, the manufacturer of insulin glargine. Dr. Rhoads has served as a consultant to Sanofi-Aventis; other authors have served as speaker, adviser, and consultant for the company.

Type 2 diabetes patients had a greater likelihood of having an acute myocardial infarction if they were treated with human neutral protamine hagedorn (NPH) insulin than if they were treated with insulin glargine, according to findings from a large retrospective study published online in the American Journal of Cardiology.

The results should be interpreted cautiously, noted the study's lead author Dr. George G. Rhoads, of the University of Medicine and Dentistry of New Jersey School of Public Health in Piscataway, and his associates.

However, they do “raise the possibility that specific insulin formulations or regimens might confer different levels of risk of [acute myocardial infarction] in patients with type 2 diabetes mellitus, and that this effect might be independent of the intensity of glucose control,” they wrote (Am. J. Cardiol. 2009;104:910-6).

The investigators culled data from the Integrated Health Care Information System, a large administrative database involving enrollees of more than 30 U.S. managed health care plans.

All the inpatient claims analyzed were for acute MIs among patients who were taking oral antidiabetic agents after initiation of either NPH, a basal insulin (5,461 patients), or insulin glargine, a newer, long-acting synthetic insulin analogue (14,730 patients). Their mean age was 56 years.

In the NPH group, significantly more patients were women and the rates of baseline comorbidities, medical claims for hypoglycemia, and medical service use for diabetes were higher, but the rates of hypertension, hyperlipidemia, and statin use were lower. The average adjusted hemoglobin A_1c was about 8% in the two groups.

During a mean 2-year follow-up period after initiating insulin treatment, the risk of an acute MI was 56% greater in the NPH group than in the glargine group.

Among the possible mechanisms that might help explain the difference was a higher rate of hypoglycemic events, according to the investigators; however, after adjustment for such events, the association did not change significantly.

There is a paucity of information on the cardiovascular safety of injectable insulin agents; and the long-term safety of NPH insulin has not been compared with that of the newer synthetic insulins.

The study was sponsored by Sanofi-Aventis, the manufacturer of insulin glargine. Dr. Rhoads has served as a consultant to Sanofi-Aventis; other authors have served as speaker, adviser, and consultant for the company.

The approved indication for exenatide was expanded with the Food and Drug Administration's approval of the glucagon-like peptide-1 (GLP-1) receptor agonist as monotherapy, as an adjunct to diet and exercise in adults with type 2 diabetes, the manufacturer announced.

Previously, exenatide (marketed as Byetta by Amylin Pharmaceuticals Inc. and Eli Lilly & Co.) was approved for type 2 diabetes in combination with diet and exercise and with other diabetes medications.

Approval was based on a study of 232 type 2 diabetes patients who did not achieve adequate glycemic control on diet and exercise alone and were randomized to treatment with one of two exenatide doses or placebo. At 24 weeks, reductions in hemoglobin A_1c levels from baseline were significantly greater among those on 5 mcg or 10 mcg of exenatide twice a day compared with those on placebo, according to the revised label.

Nausea, the most common side effect, affected 3% of those on the 5-mcg dose and 13% of those on the 10-mcg dose, according to Amylin's announcement.

In addition to the new indication, the FDA approved changes to the safety information in the exenatide label, including pancreatitis in the warnings and precautions section, which addresses a previous FDA alert, and more information about exenatide use in patients with renal impairment. There have been postmarketing reports of acute pancreatitis associated with exenatide, including cases of fatal and nonfatal hemorrhagic or necrotizing pancreatitis. The label also advises against use of exenatide in patients with severe renal impairment or end-stage renal disease and recommends that it should be used cautiously in patients who have had a kidney transplant.

Exenatide, like other GLP-1 receptors, “enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying,” according to the label. Exenatide should be injected subcutaneously within 60 minutes before morning and evening meals, or before the two main meals of the day, about 6 hours or more apart. The recommended starting dose is 5 mcg twice a day, increasing to 10 mcg twice a day after 1 month, depending on the patient's response.

The updated safety changes in the label are explained in a “Dear Health Care Professional” letter, which can be viewed at www.byettahcp.com/hcp/pdf/Dear%20HCP%20Letter.pdf

The approved indication for exenatide was expanded with the Food and Drug Administration's approval of the glucagon-like peptide-1 (GLP-1) receptor agonist as monotherapy, as an adjunct to diet and exercise in adults with type 2 diabetes, the manufacturer announced.

Previously, exenatide (marketed as Byetta by Amylin Pharmaceuticals Inc. and Eli Lilly & Co.) was approved for type 2 diabetes in combination with diet and exercise and with other diabetes medications.

Approval was based on a study of 232 type 2 diabetes patients who did not achieve adequate glycemic control on diet and exercise alone and were randomized to treatment with one of two exenatide doses or placebo. At 24 weeks, reductions in hemoglobin A_1c levels from baseline were significantly greater among those on 5 mcg or 10 mcg of exenatide twice a day compared with those on placebo, according to the revised label.

Nausea, the most common side effect, affected 3% of those on the 5-mcg dose and 13% of those on the 10-mcg dose, according to Amylin's announcement.

In addition to the new indication, the FDA approved changes to the safety information in the exenatide label, including pancreatitis in the warnings and precautions section, which addresses a previous FDA alert, and more information about exenatide use in patients with renal impairment. There have been postmarketing reports of acute pancreatitis associated with exenatide, including cases of fatal and nonfatal hemorrhagic or necrotizing pancreatitis. The label also advises against use of exenatide in patients with severe renal impairment or end-stage renal disease and recommends that it should be used cautiously in patients who have had a kidney transplant.

Exenatide, like other GLP-1 receptors, “enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying,” according to the label. Exenatide should be injected subcutaneously within 60 minutes before morning and evening meals, or before the two main meals of the day, about 6 hours or more apart. The recommended starting dose is 5 mcg twice a day, increasing to 10 mcg twice a day after 1 month, depending on the patient's response.

The updated safety changes in the label are explained in a “Dear Health Care Professional” letter, which can be viewed at www.byettahcp.com/hcp/pdf/Dear%20HCP%20Letter.pdf

The approved indication for exenatide was expanded with the Food and Drug Administration's approval of the glucagon-like peptide-1 (GLP-1) receptor agonist as monotherapy, as an adjunct to diet and exercise in adults with type 2 diabetes, the manufacturer announced.

Previously, exenatide (marketed as Byetta by Amylin Pharmaceuticals Inc. and Eli Lilly & Co.) was approved for type 2 diabetes in combination with diet and exercise and with other diabetes medications.

Approval was based on a study of 232 type 2 diabetes patients who did not achieve adequate glycemic control on diet and exercise alone and were randomized to treatment with one of two exenatide doses or placebo. At 24 weeks, reductions in hemoglobin A_1c levels from baseline were significantly greater among those on 5 mcg or 10 mcg of exenatide twice a day compared with those on placebo, according to the revised label.

Nausea, the most common side effect, affected 3% of those on the 5-mcg dose and 13% of those on the 10-mcg dose, according to Amylin's announcement.

In addition to the new indication, the FDA approved changes to the safety information in the exenatide label, including pancreatitis in the warnings and precautions section, which addresses a previous FDA alert, and more information about exenatide use in patients with renal impairment. There have been postmarketing reports of acute pancreatitis associated with exenatide, including cases of fatal and nonfatal hemorrhagic or necrotizing pancreatitis. The label also advises against use of exenatide in patients with severe renal impairment or end-stage renal disease and recommends that it should be used cautiously in patients who have had a kidney transplant.

Exenatide, like other GLP-1 receptors, “enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying,” according to the label. Exenatide should be injected subcutaneously within 60 minutes before morning and evening meals, or before the two main meals of the day, about 6 hours or more apart. The recommended starting dose is 5 mcg twice a day, increasing to 10 mcg twice a day after 1 month, depending on the patient's response.

The updated safety changes in the label are explained in a “Dear Health Care Professional” letter, which can be viewed at www.byettahcp.com/hcp/pdf/Dear%20HCP%20Letter.pdf