Elizabeth Mechcatie

ROCKVILLE, MD. — A Food and Drug Administration advisory panel unanimously recommended that the combination antihypertensive product irbesartan and hydrochlorothiazide be approved as a first-line treatment for hypertension.

The Cardiovascular and Renal Drugs Advisory Committee voted 7–0 in favor of approving the fixed-dose angiotensin receptor blocker-diuretic combination product as initial therapy.

The company has proposed that Avalide be indicated as initial treatment of severe hypertension. The panel was asked to comment on the wording of the indication statement that would be included in the label. Several were supportive of wording that Avalide can be considered as initial treatment when control of blood pressure is not likely to be achieved with one drug, or for moderate to severe hypertension.

The product, marketed as Avalide by Bristol-Myers Squibb (BMS), was approved in 1997 for treating hypertension, with a statement in its label that says the combination therapy should not be used until a patient has failed to achieve the desired effect with monotherapy.

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

The combination antihypertensives that have previously been approved as first-line treatments are Capozide (captopril and hydrochlorothiazide, or HCTZ), Ziac (bisoprolol/HCTZ), and Hyzaar (losartan/HCTZ).

At the meeting on Avalide, BMS provided the results of two studies. The first, a pivotal trial of 695 patients (mean age 52 years) with severe hypertension (an untreated diastolic blood pressure of at least 110 mm Hg or on monotherapy with a diastolic blood pressure of at least 100 mm Hg), compared Avalide with irbesartan monotherapy as initial therapy. The second, a supportive trial, compared Avalide with irbesartan and HCTZ monotherapies in patients with moderate hypertension. The studies used forced titration to 300 mg/25 mg of Avalide, 300 mg of irbesartan, or 25 mg of HCTZ.

In the pivotal trial, 47% of patients on Avalide had achieved a diastolic blood pressure below 90 mm Hg at 5 weeks, the primary end point, compared with 33% of patients on irbesartan monotherapy, which was a highly significant difference.

Among black subjects (about 14% of the subjects), 40% of those on Avalide had achieved a diastolic blood pressure below 90 mm Hg at 5 weeks, compared with nearly 15% of those on irbesartan. In diabetic subjects, 33% had achieved blood pressure below 140/90 mm Hg, compared with 23% of those on irbesartan, at 5 weeks.

Overall, Avalide was safe and well tolerated, and was comparable to irbesartan, with no increase in dizziness or syncope and no serious adverse events related to treatment. No deaths were reported, according to BMS.

About 4% of patients in each group experienced dizziness, and headache was reported in 4% of those on Avalide and 6% of those on irbesartan. Hypotension was reported in 0.6% of those on Avalide and none of those on monotherapy. About 2% in each group discontinued treatment for an adverse event.

Among the 92 patients aged 65 and older, Avalide was well tolerated, there were no cases of hypotension or syncope, and dizziness was not more common than in younger patients.

In the supportive study of about 500 patients with moderate hypertension, Avalide was more effective in reducing blood pressure than either irbesartan or HCTZ alone, had a comparable safety profile, and was well tolerated in the elderly, according to BMS.

Several panel members said the company should get more data on the combination as first-line treatment in elderly and renal dysfunction patients.

Approval as a first-line treatment would not affect Avalide's patent, which expires in 2012, a spokesperson for BMS said.

ROCKVILLE, MD. — A Food and Drug Administration advisory panel unanimously recommended that the combination antihypertensive product irbesartan and hydrochlorothiazide be approved as a first-line treatment for hypertension.

The Cardiovascular and Renal Drugs Advisory Committee voted 7–0 in favor of approving the fixed-dose angiotensin receptor blocker-diuretic combination product as initial therapy.

The company has proposed that Avalide be indicated as initial treatment of severe hypertension. The panel was asked to comment on the wording of the indication statement that would be included in the label. Several were supportive of wording that Avalide can be considered as initial treatment when control of blood pressure is not likely to be achieved with one drug, or for moderate to severe hypertension.

The product, marketed as Avalide by Bristol-Myers Squibb (BMS), was approved in 1997 for treating hypertension, with a statement in its label that says the combination therapy should not be used until a patient has failed to achieve the desired effect with monotherapy.

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

The combination antihypertensives that have previously been approved as first-line treatments are Capozide (captopril and hydrochlorothiazide, or HCTZ), Ziac (bisoprolol/HCTZ), and Hyzaar (losartan/HCTZ).

At the meeting on Avalide, BMS provided the results of two studies. The first, a pivotal trial of 695 patients (mean age 52 years) with severe hypertension (an untreated diastolic blood pressure of at least 110 mm Hg or on monotherapy with a diastolic blood pressure of at least 100 mm Hg), compared Avalide with irbesartan monotherapy as initial therapy. The second, a supportive trial, compared Avalide with irbesartan and HCTZ monotherapies in patients with moderate hypertension. The studies used forced titration to 300 mg/25 mg of Avalide, 300 mg of irbesartan, or 25 mg of HCTZ.

In the pivotal trial, 47% of patients on Avalide had achieved a diastolic blood pressure below 90 mm Hg at 5 weeks, the primary end point, compared with 33% of patients on irbesartan monotherapy, which was a highly significant difference.

Among black subjects (about 14% of the subjects), 40% of those on Avalide had achieved a diastolic blood pressure below 90 mm Hg at 5 weeks, compared with nearly 15% of those on irbesartan. In diabetic subjects, 33% had achieved blood pressure below 140/90 mm Hg, compared with 23% of those on irbesartan, at 5 weeks.

Overall, Avalide was safe and well tolerated, and was comparable to irbesartan, with no increase in dizziness or syncope and no serious adverse events related to treatment. No deaths were reported, according to BMS.

About 4% of patients in each group experienced dizziness, and headache was reported in 4% of those on Avalide and 6% of those on irbesartan. Hypotension was reported in 0.6% of those on Avalide and none of those on monotherapy. About 2% in each group discontinued treatment for an adverse event.

Among the 92 patients aged 65 and older, Avalide was well tolerated, there were no cases of hypotension or syncope, and dizziness was not more common than in younger patients.

In the supportive study of about 500 patients with moderate hypertension, Avalide was more effective in reducing blood pressure than either irbesartan or HCTZ alone, had a comparable safety profile, and was well tolerated in the elderly, according to BMS.

Several panel members said the company should get more data on the combination as first-line treatment in elderly and renal dysfunction patients.

Approval as a first-line treatment would not affect Avalide's patent, which expires in 2012, a spokesperson for BMS said.

ROCKVILLE, MD. — A Food and Drug Administration advisory panel unanimously recommended that the combination antihypertensive product irbesartan and hydrochlorothiazide be approved as a first-line treatment for hypertension.

The Cardiovascular and Renal Drugs Advisory Committee voted 7–0 in favor of approving the fixed-dose angiotensin receptor blocker-diuretic combination product as initial therapy.

The company has proposed that Avalide be indicated as initial treatment of severe hypertension. The panel was asked to comment on the wording of the indication statement that would be included in the label. Several were supportive of wording that Avalide can be considered as initial treatment when control of blood pressure is not likely to be achieved with one drug, or for moderate to severe hypertension.

The product, marketed as Avalide by Bristol-Myers Squibb (BMS), was approved in 1997 for treating hypertension, with a statement in its label that says the combination therapy should not be used until a patient has failed to achieve the desired effect with monotherapy.

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

The combination antihypertensives that have previously been approved as first-line treatments are Capozide (captopril and hydrochlorothiazide, or HCTZ), Ziac (bisoprolol/HCTZ), and Hyzaar (losartan/HCTZ).

At the meeting on Avalide, BMS provided the results of two studies. The first, a pivotal trial of 695 patients (mean age 52 years) with severe hypertension (an untreated diastolic blood pressure of at least 110 mm Hg or on monotherapy with a diastolic blood pressure of at least 100 mm Hg), compared Avalide with irbesartan monotherapy as initial therapy. The second, a supportive trial, compared Avalide with irbesartan and HCTZ monotherapies in patients with moderate hypertension. The studies used forced titration to 300 mg/25 mg of Avalide, 300 mg of irbesartan, or 25 mg of HCTZ.

In the pivotal trial, 47% of patients on Avalide had achieved a diastolic blood pressure below 90 mm Hg at 5 weeks, the primary end point, compared with 33% of patients on irbesartan monotherapy, which was a highly significant difference.

Among black subjects (about 14% of the subjects), 40% of those on Avalide had achieved a diastolic blood pressure below 90 mm Hg at 5 weeks, compared with nearly 15% of those on irbesartan. In diabetic subjects, 33% had achieved blood pressure below 140/90 mm Hg, compared with 23% of those on irbesartan, at 5 weeks.

Overall, Avalide was safe and well tolerated, and was comparable to irbesartan, with no increase in dizziness or syncope and no serious adverse events related to treatment. No deaths were reported, according to BMS.

About 4% of patients in each group experienced dizziness, and headache was reported in 4% of those on Avalide and 6% of those on irbesartan. Hypotension was reported in 0.6% of those on Avalide and none of those on monotherapy. About 2% in each group discontinued treatment for an adverse event.

Among the 92 patients aged 65 and older, Avalide was well tolerated, there were no cases of hypotension or syncope, and dizziness was not more common than in younger patients.

In the supportive study of about 500 patients with moderate hypertension, Avalide was more effective in reducing blood pressure than either irbesartan or HCTZ alone, had a comparable safety profile, and was well tolerated in the elderly, according to BMS.

Several panel members said the company should get more data on the combination as first-line treatment in elderly and renal dysfunction patients.

Approval as a first-line treatment would not affect Avalide's patent, which expires in 2012, a spokesperson for BMS said.

The Food and Drug Administration has approved atorvastatin for five new indications in adults with coronary heart disease, based on findings in the Treating to New Targets trial.

The approval, issued in March, was for reducing the risk of nonfatal myocardial infarction, fatal and nonfatal stroke, angina, revascularization procedures, and hospitalization for heart failure, in patients with clinically evident coronary heart disease.

In the Treating to New Targets (TNT) trial, the 80-mg daily dosage of atorvastatin was associated with a significantly greater reduction in the risk of events that make up the five new indications, compared with the 10-mg dose, over a median of almost 5 years in 10,001 patients.

The primary end point was time to occurrence of any of these major cardiovascular events: death resulting from CHD, nonfatal MI, resuscitated cardiac arrest, and fatal and nonfatal stroke. There were 434 such events among those on 80 mg/day, versus 548 such events among those on 10 mg/day, translating to a relative risk reduction of 22%—a highly significant difference. This overall reduction in risk was consistent, regardless of gender or whether patients were younger than age 65 or aged 65 years and older. As for individual events, the rate of nonfatal, non-procedure-related MI and fatal and nonfatal stroke was significantly reduced in the 80-mg/day group, when compared with placebo, but neither CHD death nor resuscitated cardiac arrest was significantly reduced, according to the revised package label for atorvastatin, which is marketed as Lipitor by Pfizer.

The 80-mg/day dose also significantly reduced some secondary end points: the rate of coronary revascularization, angina, and hospitalization for heart failure. The rate of heart failure hospitalization was lower with atorvastatin 80 mg/day, but only in the 8% of patients with a history of heart failure. All-cause mortality was not significantly different in the two groups, according to the drug's revised label. Those on 80 mg of atorvastatin per day had more serious adverse events (2%) and discontinuations because of adverse events (10%) over 5 years, compared with those on the 10-mg dose (1% and 8%, respectively), according to the drug's revised label.

Noting that atherosclerosis is not just a disease of the large coronary arteries, but involves the smaller vessels as well, Dr. Ann Bolger, professor of clinical medicine at the University of California, San Francisco, said in an interview that reducing the lipid burden and reducing inflammation with statins seem to decrease the incidence of cardiovascular events, which usually start at the endothelial level.

The Food and Drug Administration has approved atorvastatin for five new indications in adults with coronary heart disease, based on findings in the Treating to New Targets trial.

The approval, issued in March, was for reducing the risk of nonfatal myocardial infarction, fatal and nonfatal stroke, angina, revascularization procedures, and hospitalization for heart failure, in patients with clinically evident coronary heart disease.

In the Treating to New Targets (TNT) trial, the 80-mg daily dosage of atorvastatin was associated with a significantly greater reduction in the risk of events that make up the five new indications, compared with the 10-mg dose, over a median of almost 5 years in 10,001 patients.

The primary end point was time to occurrence of any of these major cardiovascular events: death resulting from CHD, nonfatal MI, resuscitated cardiac arrest, and fatal and nonfatal stroke. There were 434 such events among those on 80 mg/day, versus 548 such events among those on 10 mg/day, translating to a relative risk reduction of 22%—a highly significant difference. This overall reduction in risk was consistent, regardless of gender or whether patients were younger than age 65 or aged 65 years and older. As for individual events, the rate of nonfatal, non-procedure-related MI and fatal and nonfatal stroke was significantly reduced in the 80-mg/day group, when compared with placebo, but neither CHD death nor resuscitated cardiac arrest was significantly reduced, according to the revised package label for atorvastatin, which is marketed as Lipitor by Pfizer.

The 80-mg/day dose also significantly reduced some secondary end points: the rate of coronary revascularization, angina, and hospitalization for heart failure. The rate of heart failure hospitalization was lower with atorvastatin 80 mg/day, but only in the 8% of patients with a history of heart failure. All-cause mortality was not significantly different in the two groups, according to the drug's revised label. Those on 80 mg of atorvastatin per day had more serious adverse events (2%) and discontinuations because of adverse events (10%) over 5 years, compared with those on the 10-mg dose (1% and 8%, respectively), according to the drug's revised label.

Noting that atherosclerosis is not just a disease of the large coronary arteries, but involves the smaller vessels as well, Dr. Ann Bolger, professor of clinical medicine at the University of California, San Francisco, said in an interview that reducing the lipid burden and reducing inflammation with statins seem to decrease the incidence of cardiovascular events, which usually start at the endothelial level.

The Food and Drug Administration has approved atorvastatin for five new indications in adults with coronary heart disease, based on findings in the Treating to New Targets trial.

The approval, issued in March, was for reducing the risk of nonfatal myocardial infarction, fatal and nonfatal stroke, angina, revascularization procedures, and hospitalization for heart failure, in patients with clinically evident coronary heart disease.

In the Treating to New Targets (TNT) trial, the 80-mg daily dosage of atorvastatin was associated with a significantly greater reduction in the risk of events that make up the five new indications, compared with the 10-mg dose, over a median of almost 5 years in 10,001 patients.

The primary end point was time to occurrence of any of these major cardiovascular events: death resulting from CHD, nonfatal MI, resuscitated cardiac arrest, and fatal and nonfatal stroke. There were 434 such events among those on 80 mg/day, versus 548 such events among those on 10 mg/day, translating to a relative risk reduction of 22%—a highly significant difference. This overall reduction in risk was consistent, regardless of gender or whether patients were younger than age 65 or aged 65 years and older. As for individual events, the rate of nonfatal, non-procedure-related MI and fatal and nonfatal stroke was significantly reduced in the 80-mg/day group, when compared with placebo, but neither CHD death nor resuscitated cardiac arrest was significantly reduced, according to the revised package label for atorvastatin, which is marketed as Lipitor by Pfizer.

The 80-mg/day dose also significantly reduced some secondary end points: the rate of coronary revascularization, angina, and hospitalization for heart failure. The rate of heart failure hospitalization was lower with atorvastatin 80 mg/day, but only in the 8% of patients with a history of heart failure. All-cause mortality was not significantly different in the two groups, according to the drug's revised label. Those on 80 mg of atorvastatin per day had more serious adverse events (2%) and discontinuations because of adverse events (10%) over 5 years, compared with those on the 10-mg dose (1% and 8%, respectively), according to the drug's revised label.

Noting that atherosclerosis is not just a disease of the large coronary arteries, but involves the smaller vessels as well, Dr. Ann Bolger, professor of clinical medicine at the University of California, San Francisco, said in an interview that reducing the lipid burden and reducing inflammation with statins seem to decrease the incidence of cardiovascular events, which usually start at the endothelial level.

Warnings about the risks of complex sleep-related behaviors such as driving while asleep, and about serious allergic reactions that have recently been associated with sleep drugs, are being added to their labels, at the request of the Food and Drug Administration.

The FDA announced that the manufacturers of the 13 approved sedative hypnotics, which include older drugs such as Dalmane and newer drugs such as Ambien and Lunesta, had been asked to describe cases of anaphylaxis and angioedema, and cases of complex sleep-related behaviors in their labels. In addition, the drugmakers have begun sending out “Dear Health Care Provider” letters describing these adverse events and the label changes.

The need for these changes are based on postmarketing reports of these events, “which we believe are serious and about which practitioners and patients need to know,” Dr. Russell Katz, director of the FDA's division of neurology products, said during an FDA teleconference.

After receiving postmarketing reports of angioedema and anaphylaxis in people on the most recently approved hypnotic, ramelteon (Rozerem), the FDA reviewed the entire class for this effect and found similar cases. The review of complex sleep-related behaviors—which include driving, making phone calls, preparing and eating food, and having sex, all while asleep—began after such cases were publicized about 1 year ago. Although such cases can be difficult to interpret, “we believe the entire class is capable of producing those events as well,” Dr. Katz said. Physicians should advise patients that the complex sleep behaviors are more likely to occur when people take higher than normal doses, and when they take these drugs with other drugs that can affect the nervous system or with alcohol, he added.

Dr. Katz described both types of events as “relatively rare,” based on the information available. He added that no deaths have been reported in association with any of the events reported to the FDA.

After the teleconference, an FDA spokesperson said that the agency had received a “couple of dozen” reports of complex sleep behaviors but emphasized that these events are likely to be underreported, and that the decision to strengthen labeling was not based on numbers but on the serious nature of these adverse effects. There were more cases of allergic reactions, but no specific numbers were provided.

Manufacturers also have been asked to develop “Patient Medication Guides” to directly inform patients about the risks and about what they can do to minimize their risks of experiencing these events. Medication guides are leaflets that are required for certain drugs with particular risks, which are distributed with each new prescription or refill. These will not be available soon, however, since the companies have until May to submit their versions of the guides, which will then need to be reviewed by the agency.

But the events also are being added to the “information for patients” section of the drug labels, which physicians can use to counsel patients. “Patients should be aware that there are behaviors that they can engage in that can decrease the risk of these events occurring, namely, to refrain from alcohol [and] other drugs that depress the nervous system and to make sure they take the right dose,” Dr. Katz emphasized.

The label change affects drugs including zolpidem (Ambien/Ambien CR, Sanofi Aventis), butabarbital (Butisol Sodium, Medpointe Pharmaceuticals HLC), flurazepam (Dalmane, Valeant Pharmaceuticals), ramelteon (Rozerem, Takeda Pharmaceutical Inc.), eszopiclone (Lunesta, Sepracor Inc.), and zaleplon (Sonata, King Pharmaceuticals Inc.).

Health care professionals can report serious adverse reactions to these and other drugs to the FDA's Medwatch program online at www.fda.gov/medwatch

Warnings about the risks of complex sleep-related behaviors such as driving while asleep, and about serious allergic reactions that have recently been associated with sleep drugs, are being added to their labels, at the request of the Food and Drug Administration.

The FDA announced that the manufacturers of the 13 approved sedative hypnotics, which include older drugs such as Dalmane and newer drugs such as Ambien and Lunesta, had been asked to describe cases of anaphylaxis and angioedema, and cases of complex sleep-related behaviors in their labels. In addition, the drugmakers have begun sending out “Dear Health Care Provider” letters describing these adverse events and the label changes.

The need for these changes are based on postmarketing reports of these events, “which we believe are serious and about which practitioners and patients need to know,” Dr. Russell Katz, director of the FDA's division of neurology products, said during an FDA teleconference.

After receiving postmarketing reports of angioedema and anaphylaxis in people on the most recently approved hypnotic, ramelteon (Rozerem), the FDA reviewed the entire class for this effect and found similar cases. The review of complex sleep-related behaviors—which include driving, making phone calls, preparing and eating food, and having sex, all while asleep—began after such cases were publicized about 1 year ago. Although such cases can be difficult to interpret, “we believe the entire class is capable of producing those events as well,” Dr. Katz said. Physicians should advise patients that the complex sleep behaviors are more likely to occur when people take higher than normal doses, and when they take these drugs with other drugs that can affect the nervous system or with alcohol, he added.

Dr. Katz described both types of events as “relatively rare,” based on the information available. He added that no deaths have been reported in association with any of the events reported to the FDA.

After the teleconference, an FDA spokesperson said that the agency had received a “couple of dozen” reports of complex sleep behaviors but emphasized that these events are likely to be underreported, and that the decision to strengthen labeling was not based on numbers but on the serious nature of these adverse effects. There were more cases of allergic reactions, but no specific numbers were provided.

Manufacturers also have been asked to develop “Patient Medication Guides” to directly inform patients about the risks and about what they can do to minimize their risks of experiencing these events. Medication guides are leaflets that are required for certain drugs with particular risks, which are distributed with each new prescription or refill. These will not be available soon, however, since the companies have until May to submit their versions of the guides, which will then need to be reviewed by the agency.

But the events also are being added to the “information for patients” section of the drug labels, which physicians can use to counsel patients. “Patients should be aware that there are behaviors that they can engage in that can decrease the risk of these events occurring, namely, to refrain from alcohol [and] other drugs that depress the nervous system and to make sure they take the right dose,” Dr. Katz emphasized.

The label change affects drugs including zolpidem (Ambien/Ambien CR, Sanofi Aventis), butabarbital (Butisol Sodium, Medpointe Pharmaceuticals HLC), flurazepam (Dalmane, Valeant Pharmaceuticals), ramelteon (Rozerem, Takeda Pharmaceutical Inc.), eszopiclone (Lunesta, Sepracor Inc.), and zaleplon (Sonata, King Pharmaceuticals Inc.).

Health care professionals can report serious adverse reactions to these and other drugs to the FDA's Medwatch program online at www.fda.gov/medwatch

Warnings about the risks of complex sleep-related behaviors such as driving while asleep, and about serious allergic reactions that have recently been associated with sleep drugs, are being added to their labels, at the request of the Food and Drug Administration.

The FDA announced that the manufacturers of the 13 approved sedative hypnotics, which include older drugs such as Dalmane and newer drugs such as Ambien and Lunesta, had been asked to describe cases of anaphylaxis and angioedema, and cases of complex sleep-related behaviors in their labels. In addition, the drugmakers have begun sending out “Dear Health Care Provider” letters describing these adverse events and the label changes.

The need for these changes are based on postmarketing reports of these events, “which we believe are serious and about which practitioners and patients need to know,” Dr. Russell Katz, director of the FDA's division of neurology products, said during an FDA teleconference.

After receiving postmarketing reports of angioedema and anaphylaxis in people on the most recently approved hypnotic, ramelteon (Rozerem), the FDA reviewed the entire class for this effect and found similar cases. The review of complex sleep-related behaviors—which include driving, making phone calls, preparing and eating food, and having sex, all while asleep—began after such cases were publicized about 1 year ago. Although such cases can be difficult to interpret, “we believe the entire class is capable of producing those events as well,” Dr. Katz said. Physicians should advise patients that the complex sleep behaviors are more likely to occur when people take higher than normal doses, and when they take these drugs with other drugs that can affect the nervous system or with alcohol, he added.

Dr. Katz described both types of events as “relatively rare,” based on the information available. He added that no deaths have been reported in association with any of the events reported to the FDA.

After the teleconference, an FDA spokesperson said that the agency had received a “couple of dozen” reports of complex sleep behaviors but emphasized that these events are likely to be underreported, and that the decision to strengthen labeling was not based on numbers but on the serious nature of these adverse effects. There were more cases of allergic reactions, but no specific numbers were provided.

Manufacturers also have been asked to develop “Patient Medication Guides” to directly inform patients about the risks and about what they can do to minimize their risks of experiencing these events. Medication guides are leaflets that are required for certain drugs with particular risks, which are distributed with each new prescription or refill. These will not be available soon, however, since the companies have until May to submit their versions of the guides, which will then need to be reviewed by the agency.

But the events also are being added to the “information for patients” section of the drug labels, which physicians can use to counsel patients. “Patients should be aware that there are behaviors that they can engage in that can decrease the risk of these events occurring, namely, to refrain from alcohol [and] other drugs that depress the nervous system and to make sure they take the right dose,” Dr. Katz emphasized.

The label change affects drugs including zolpidem (Ambien/Ambien CR, Sanofi Aventis), butabarbital (Butisol Sodium, Medpointe Pharmaceuticals HLC), flurazepam (Dalmane, Valeant Pharmaceuticals), ramelteon (Rozerem, Takeda Pharmaceutical Inc.), eszopiclone (Lunesta, Sepracor Inc.), and zaleplon (Sonata, King Pharmaceuticals Inc.).

Health care professionals can report serious adverse reactions to these and other drugs to the FDA's Medwatch program online at www.fda.gov/medwatch

GAITHERSBURG, MD. — There have been no unexpected safety findings in the early phases of two postmarketing studies of the vagus nerve stimulation device in patients with depression, according to the manufacturer.

Updates on the studies of the implantable vagus nerve stimulation (VNS) system in patients with treatment-resistant depression were provided by the manufacturer, Cyberonics, and the Food and Drug Administration during a meeting of the FDA's Neurological Devices Panel in January.

In July 2005, the VNS device, previously approved for treating seizures, was approved for adjunctive long-term treatment of chronic or recurrent depression in patients aged 18 years and older who are experiencing a major depressive episode and have not had an adequate response to four or more antidepressant treatments.

The approval came with several conditions, including that Cyberonics conduct a 1-year randomized dose-ranging study and a 5-year observational registry study.

Health advocacy groups have questioned the FDA's decision to approve the device for depression. A U.S. Senate Finance Committee investigation concluded last year that the device had been approved for the depression indication over the objections of FDA staff scientists and medical officers.

As of Dec. 31, 2006, 89 patients had been enrolled in the 1-year study, a multicenter, double-blind trial comparing the safety and effectiveness of adjunctive VNS administered at three electrical charges for 54 weeks in patients with treatment-resistant depression (TRD). The study is supposed to enroll 460 patients at 30 sites, but because of problems with reimbursement for the device and implantation surgery, the company is planning a voluntary program to donate the device and surgery so that the study can be completed in time, said Dr. Richard Rudolph, vice president of clinical and medical affairs, and chief medical officer at Cyberonics.

After the panel meeting, the Centers for Medicare and Medicaid Services said there was sufficient evidence to show vagus nerve stimulation was neither reasonable nor necessary for treating resistant depression. The agency said it planned to issue a national noncoverage determination for the use of VNS for this indication and requested public comments. VNS is covered by Medicare and Medicaid when used for epilepsy.

The 18-month report Cyberonics submitted to the FDA included serious adverse events reported through Jan. 9: There was one report of worsening depression after implantation, compared with five before implantation. There were no reports of suicide ideation after implantation, compared with one before implantation. There has been one case each reported in patients after implantation of suicide attempt, wound infection, chest pain, death (a motor vehicle accident), and thyroid carcinoma, compared with no such cases reported preimplantation, Dr. Rudolph said. The FDA presented the same data.

To date, enrollment in the registry is on schedule, he said. As of Dec. 31, 264 patients (223 with implants) had been enrolled in the long-term prospective, observational, multicenter, patient outcome registry, which is following the clinical course and outcomes for patients with TRD, with and without adjunctive VNS therapy. The plan is to enroll 1,000 patients who receive VNS and follow them for 60 months, along with 1,000 patients with treatment-resistant depression who do not receive VNS, who will be followed for 24 months or 60 months.

During the public hearing session of the meeting, Diana Zuckerman, Ph.D., president of the National Research Center for Women and Families, said postmarketing studies were critical because approval of the VNS device for depression was based on weak research. Dr. Peter Lurie of Public Citizen's Health Research Group said the need for a study comparing different electrical charges indicated the data submitted for approval were inadequate and that VNSefficacy will remain unresolved because the registry is uncontrolled and unblinded.

Postmarketing studies are critical because approval of the VNS device for depression was based on weak research. DR. ZUCKERMAN

GAITHERSBURG, MD. — There have been no unexpected safety findings in the early phases of two postmarketing studies of the vagus nerve stimulation device in patients with depression, according to the manufacturer.

Updates on the studies of the implantable vagus nerve stimulation (VNS) system in patients with treatment-resistant depression were provided by the manufacturer, Cyberonics, and the Food and Drug Administration during a meeting of the FDA's Neurological Devices Panel in January.

In July 2005, the VNS device, previously approved for treating seizures, was approved for adjunctive long-term treatment of chronic or recurrent depression in patients aged 18 years and older who are experiencing a major depressive episode and have not had an adequate response to four or more antidepressant treatments.

The approval came with several conditions, including that Cyberonics conduct a 1-year randomized dose-ranging study and a 5-year observational registry study.

Health advocacy groups have questioned the FDA's decision to approve the device for depression. A U.S. Senate Finance Committee investigation concluded last year that the device had been approved for the depression indication over the objections of FDA staff scientists and medical officers.

As of Dec. 31, 2006, 89 patients had been enrolled in the 1-year study, a multicenter, double-blind trial comparing the safety and effectiveness of adjunctive VNS administered at three electrical charges for 54 weeks in patients with treatment-resistant depression (TRD). The study is supposed to enroll 460 patients at 30 sites, but because of problems with reimbursement for the device and implantation surgery, the company is planning a voluntary program to donate the device and surgery so that the study can be completed in time, said Dr. Richard Rudolph, vice president of clinical and medical affairs, and chief medical officer at Cyberonics.

After the panel meeting, the Centers for Medicare and Medicaid Services said there was sufficient evidence to show vagus nerve stimulation was neither reasonable nor necessary for treating resistant depression. The agency said it planned to issue a national noncoverage determination for the use of VNS for this indication and requested public comments. VNS is covered by Medicare and Medicaid when used for epilepsy.

The 18-month report Cyberonics submitted to the FDA included serious adverse events reported through Jan. 9: There was one report of worsening depression after implantation, compared with five before implantation. There were no reports of suicide ideation after implantation, compared with one before implantation. There has been one case each reported in patients after implantation of suicide attempt, wound infection, chest pain, death (a motor vehicle accident), and thyroid carcinoma, compared with no such cases reported preimplantation, Dr. Rudolph said. The FDA presented the same data.

To date, enrollment in the registry is on schedule, he said. As of Dec. 31, 264 patients (223 with implants) had been enrolled in the long-term prospective, observational, multicenter, patient outcome registry, which is following the clinical course and outcomes for patients with TRD, with and without adjunctive VNS therapy. The plan is to enroll 1,000 patients who receive VNS and follow them for 60 months, along with 1,000 patients with treatment-resistant depression who do not receive VNS, who will be followed for 24 months or 60 months.

During the public hearing session of the meeting, Diana Zuckerman, Ph.D., president of the National Research Center for Women and Families, said postmarketing studies were critical because approval of the VNS device for depression was based on weak research. Dr. Peter Lurie of Public Citizen's Health Research Group said the need for a study comparing different electrical charges indicated the data submitted for approval were inadequate and that VNSefficacy will remain unresolved because the registry is uncontrolled and unblinded.

Postmarketing studies are critical because approval of the VNS device for depression was based on weak research. DR. ZUCKERMAN

GAITHERSBURG, MD. — There have been no unexpected safety findings in the early phases of two postmarketing studies of the vagus nerve stimulation device in patients with depression, according to the manufacturer.

Updates on the studies of the implantable vagus nerve stimulation (VNS) system in patients with treatment-resistant depression were provided by the manufacturer, Cyberonics, and the Food and Drug Administration during a meeting of the FDA's Neurological Devices Panel in January.

In July 2005, the VNS device, previously approved for treating seizures, was approved for adjunctive long-term treatment of chronic or recurrent depression in patients aged 18 years and older who are experiencing a major depressive episode and have not had an adequate response to four or more antidepressant treatments.

The approval came with several conditions, including that Cyberonics conduct a 1-year randomized dose-ranging study and a 5-year observational registry study.

Health advocacy groups have questioned the FDA's decision to approve the device for depression. A U.S. Senate Finance Committee investigation concluded last year that the device had been approved for the depression indication over the objections of FDA staff scientists and medical officers.

As of Dec. 31, 2006, 89 patients had been enrolled in the 1-year study, a multicenter, double-blind trial comparing the safety and effectiveness of adjunctive VNS administered at three electrical charges for 54 weeks in patients with treatment-resistant depression (TRD). The study is supposed to enroll 460 patients at 30 sites, but because of problems with reimbursement for the device and implantation surgery, the company is planning a voluntary program to donate the device and surgery so that the study can be completed in time, said Dr. Richard Rudolph, vice president of clinical and medical affairs, and chief medical officer at Cyberonics.

After the panel meeting, the Centers for Medicare and Medicaid Services said there was sufficient evidence to show vagus nerve stimulation was neither reasonable nor necessary for treating resistant depression. The agency said it planned to issue a national noncoverage determination for the use of VNS for this indication and requested public comments. VNS is covered by Medicare and Medicaid when used for epilepsy.

The 18-month report Cyberonics submitted to the FDA included serious adverse events reported through Jan. 9: There was one report of worsening depression after implantation, compared with five before implantation. There were no reports of suicide ideation after implantation, compared with one before implantation. There has been one case each reported in patients after implantation of suicide attempt, wound infection, chest pain, death (a motor vehicle accident), and thyroid carcinoma, compared with no such cases reported preimplantation, Dr. Rudolph said. The FDA presented the same data.

To date, enrollment in the registry is on schedule, he said. As of Dec. 31, 264 patients (223 with implants) had been enrolled in the long-term prospective, observational, multicenter, patient outcome registry, which is following the clinical course and outcomes for patients with TRD, with and without adjunctive VNS therapy. The plan is to enroll 1,000 patients who receive VNS and follow them for 60 months, along with 1,000 patients with treatment-resistant depression who do not receive VNS, who will be followed for 24 months or 60 months.

During the public hearing session of the meeting, Diana Zuckerman, Ph.D., president of the National Research Center for Women and Families, said postmarketing studies were critical because approval of the VNS device for depression was based on weak research. Dr. Peter Lurie of Public Citizen's Health Research Group said the need for a study comparing different electrical charges indicated the data submitted for approval were inadequate and that VNSefficacy will remain unresolved because the registry is uncontrolled and unblinded.

Postmarketing studies are critical because approval of the VNS device for depression was based on weak research. DR. ZUCKERMAN

ROCKVILLE, MD. — Pediatric information in drug labels should be easier to find and understand thanks to a new way of incorporating pediatric information into a revised drug label design, required for all new drugs approved since June last year.

At a meeting of the Food and Drug Administration's Pediatric Advisory Committee held to review pediatric adverse event reports for several drugs, Iris Masucci, Pharm.D., of the FDA's Center for Drug Evaluation and Research (CDER), provided an overview of the elements of the revised drug label.

A physician labeling rule implemented in June 2006 requires that drug labels be more user friendly. The label, or package insert, of any newly approved drug or biologic or supplemental efficacy approval of a drug submitted to the FDA after June 30, 2006, is required to be in the new format. Drugs approved in the 5 years before this date must update their labeling to the new format according to a stepped timeline.

Drugs approved before that time are not required to make the change, but may do so voluntarily. The new labeling requirements also apply to biologics.

The approach on where to incorporate pediatric information into labels is a separate initiative from the new labeling format requirements. Rather, it is a more clearly defined paradigm than what has been used in the past, which will make labels more consistent in terms of how and where pediatric information is added, Dr. Masucci said in an interview.

A major change in the newly designed label is the highlights section, designed in response to feedback from physicians on what they wanted in a drug label, which appears at the beginning of the label. This is a half-page summary that provides the main information on a drug in a simple format with bullets and tables, Dr. Masucci said at the meeting.

This section includes the name of the product with the date of the initial U.S. approval; a boxed warning (if there is one); indications (which include the pharmacologic class of the drug); usage, dosage, and administration information; major changes recently made to the label; as well as dosage forms and strengths, contraindications, warning and precautions, adverse reactions, and drug interactions. Also included is a patient counseling information statement and a section on use in specific populations, such as children.

The contents of the label include numbered sections with a specific number that corresponds to a particular section, which will be consistent for all drugs. For example, section 2 will always pertain to dosage and administration, and section 8 will always pertain to use in specific populations, which includes pediatric patients.

Other features of the new label include the consolidation of the warnings and precautions sections. Sections on drug interactions, use in specific populations, and patient counseling information—which appears in the precautions section in the old label—are now separate sections. Also, sections on clinical studies and nonclinical toxicology, previously optional, are now required, she said.

Contact information for the FDA's adverse event reporting program, MedWatch, and the drug's manufacturer for reporting adverse events are now also included in the label.

With the old format, it is difficult to know if a drug is actually approved for pediatric use, Dr. Masucci said, noting that in some tables, a pediatric dose but no pediatric data are listed.

If the new data warrant a pediatric indication, the pediatric information is included in the applicable sections: indications and usage, dosage and administration, adverse reactions, use in specific populations, pharmacokinetics and pharmacodynamics, and clinical studies. However, if the data do not support pediatric approval, all pediatric information on the drug appears in the section “Use in specific populations-Pediatric Use,” which she said “will avoid the implication of approval.”

ROCKVILLE, MD. — Pediatric information in drug labels should be easier to find and understand thanks to a new way of incorporating pediatric information into a revised drug label design, required for all new drugs approved since June last year.

At a meeting of the Food and Drug Administration's Pediatric Advisory Committee held to review pediatric adverse event reports for several drugs, Iris Masucci, Pharm.D., of the FDA's Center for Drug Evaluation and Research (CDER), provided an overview of the elements of the revised drug label.

A physician labeling rule implemented in June 2006 requires that drug labels be more user friendly. The label, or package insert, of any newly approved drug or biologic or supplemental efficacy approval of a drug submitted to the FDA after June 30, 2006, is required to be in the new format. Drugs approved in the 5 years before this date must update their labeling to the new format according to a stepped timeline.

Drugs approved before that time are not required to make the change, but may do so voluntarily. The new labeling requirements also apply to biologics.

The approach on where to incorporate pediatric information into labels is a separate initiative from the new labeling format requirements. Rather, it is a more clearly defined paradigm than what has been used in the past, which will make labels more consistent in terms of how and where pediatric information is added, Dr. Masucci said in an interview.

A major change in the newly designed label is the highlights section, designed in response to feedback from physicians on what they wanted in a drug label, which appears at the beginning of the label. This is a half-page summary that provides the main information on a drug in a simple format with bullets and tables, Dr. Masucci said at the meeting.

This section includes the name of the product with the date of the initial U.S. approval; a boxed warning (if there is one); indications (which include the pharmacologic class of the drug); usage, dosage, and administration information; major changes recently made to the label; as well as dosage forms and strengths, contraindications, warning and precautions, adverse reactions, and drug interactions. Also included is a patient counseling information statement and a section on use in specific populations, such as children.

The contents of the label include numbered sections with a specific number that corresponds to a particular section, which will be consistent for all drugs. For example, section 2 will always pertain to dosage and administration, and section 8 will always pertain to use in specific populations, which includes pediatric patients.

Other features of the new label include the consolidation of the warnings and precautions sections. Sections on drug interactions, use in specific populations, and patient counseling information—which appears in the precautions section in the old label—are now separate sections. Also, sections on clinical studies and nonclinical toxicology, previously optional, are now required, she said.

Contact information for the FDA's adverse event reporting program, MedWatch, and the drug's manufacturer for reporting adverse events are now also included in the label.

With the old format, it is difficult to know if a drug is actually approved for pediatric use, Dr. Masucci said, noting that in some tables, a pediatric dose but no pediatric data are listed.

If the new data warrant a pediatric indication, the pediatric information is included in the applicable sections: indications and usage, dosage and administration, adverse reactions, use in specific populations, pharmacokinetics and pharmacodynamics, and clinical studies. However, if the data do not support pediatric approval, all pediatric information on the drug appears in the section “Use in specific populations-Pediatric Use,” which she said “will avoid the implication of approval.”

ROCKVILLE, MD. — Pediatric information in drug labels should be easier to find and understand thanks to a new way of incorporating pediatric information into a revised drug label design, required for all new drugs approved since June last year.

At a meeting of the Food and Drug Administration's Pediatric Advisory Committee held to review pediatric adverse event reports for several drugs, Iris Masucci, Pharm.D., of the FDA's Center for Drug Evaluation and Research (CDER), provided an overview of the elements of the revised drug label.

A physician labeling rule implemented in June 2006 requires that drug labels be more user friendly. The label, or package insert, of any newly approved drug or biologic or supplemental efficacy approval of a drug submitted to the FDA after June 30, 2006, is required to be in the new format. Drugs approved in the 5 years before this date must update their labeling to the new format according to a stepped timeline.

Drugs approved before that time are not required to make the change, but may do so voluntarily. The new labeling requirements also apply to biologics.

The approach on where to incorporate pediatric information into labels is a separate initiative from the new labeling format requirements. Rather, it is a more clearly defined paradigm than what has been used in the past, which will make labels more consistent in terms of how and where pediatric information is added, Dr. Masucci said in an interview.

A major change in the newly designed label is the highlights section, designed in response to feedback from physicians on what they wanted in a drug label, which appears at the beginning of the label. This is a half-page summary that provides the main information on a drug in a simple format with bullets and tables, Dr. Masucci said at the meeting.

This section includes the name of the product with the date of the initial U.S. approval; a boxed warning (if there is one); indications (which include the pharmacologic class of the drug); usage, dosage, and administration information; major changes recently made to the label; as well as dosage forms and strengths, contraindications, warning and precautions, adverse reactions, and drug interactions. Also included is a patient counseling information statement and a section on use in specific populations, such as children.

The contents of the label include numbered sections with a specific number that corresponds to a particular section, which will be consistent for all drugs. For example, section 2 will always pertain to dosage and administration, and section 8 will always pertain to use in specific populations, which includes pediatric patients.

Other features of the new label include the consolidation of the warnings and precautions sections. Sections on drug interactions, use in specific populations, and patient counseling information—which appears in the precautions section in the old label—are now separate sections. Also, sections on clinical studies and nonclinical toxicology, previously optional, are now required, she said.

Contact information for the FDA's adverse event reporting program, MedWatch, and the drug's manufacturer for reporting adverse events are now also included in the label.

With the old format, it is difficult to know if a drug is actually approved for pediatric use, Dr. Masucci said, noting that in some tables, a pediatric dose but no pediatric data are listed.

If the new data warrant a pediatric indication, the pediatric information is included in the applicable sections: indications and usage, dosage and administration, adverse reactions, use in specific populations, pharmacokinetics and pharmacodynamics, and clinical studies. However, if the data do not support pediatric approval, all pediatric information on the drug appears in the section “Use in specific populations-Pediatric Use,” which she said “will avoid the implication of approval.”

The Food and Drug Administration's latest approval of a carotid stent system came with a list of postmarketing study commitments that includes monitoring outcomes in recipients and evaluating training programs for physicians using the device.

In January, the FDA approved the Protégé GPS and Protégé RX carotid stent systems for treating patients with carotid artery disease who are at high risk for adverse events from carotid endarterectomy. The FDA requires use of the embolic protection devices made by the same company, approved by the FDA in February 2006, with the stent.

Candidates for the stent must meet the following criteria:

▸ They must have stenosis of the common or internal carotid artery measuring 50% or greater if they are symptomatic, or 80% or greater if they are asymptomatic (as determined by ultrasound or angiography).

▸ They must have a reference vessel diameter within the range of 4.5 mm and 9.5 mm at the target lesion.

The Protégé carotid stent system, with the embolic protection device, was studied in the prospective, nonrandomized, multicenter Carotid Revascularization With ev3 Inc. Arterial Technology Evolution (CREATE) trial of 419 patients with carotid artery disease who were at risk for stoke and at high risk for adverse events from surgery.

The risk of death, stroke, and MI at 30 days, or any stroke in the area of the blockage at 1 year, was similar to the rate of complications reported in the literature from patients undergoing surgery, according to the FDA. The study also showed that the stent still maintained blood flow to the brain more than 1 year after the procedure.

As part of the approval, the manufacturer, ev3, has agreed to conduct a long-term follow-up study of patients from the CREATE study to evaluate the effectiveness and safety of the stent through 3 years after its implantation, according to the FDA approval letter. This will include performing a clinical exam, carotid duplex ultrasound, and neurologic exam annually. The company also will conduct a postapproval study of at least 1,500 patients from high-, moderate-, and low-volume centers who were treated by physicians with different categories of training. The study will evaluate the composite rate of death, ipsilateral cerebrovascular accident (CVA), procedure-related CVA, or MI 30 days after the procedure in 1,000 patients. This study also will follow these patients and determine the rate of ipsilateral stroke at 12 months.

Plymouth, Minn.-based ev3 Inc. manufactures the stents and the distal filter embolic protection device. The filter is marketed as the SpiderRX Embolic Protection Device.

The Food and Drug Administration's latest approval of a carotid stent system came with a list of postmarketing study commitments that includes monitoring outcomes in recipients and evaluating training programs for physicians using the device.

In January, the FDA approved the Protégé GPS and Protégé RX carotid stent systems for treating patients with carotid artery disease who are at high risk for adverse events from carotid endarterectomy. The FDA requires use of the embolic protection devices made by the same company, approved by the FDA in February 2006, with the stent.

Candidates for the stent must meet the following criteria:

▸ They must have stenosis of the common or internal carotid artery measuring 50% or greater if they are symptomatic, or 80% or greater if they are asymptomatic (as determined by ultrasound or angiography).

▸ They must have a reference vessel diameter within the range of 4.5 mm and 9.5 mm at the target lesion.

The Protégé carotid stent system, with the embolic protection device, was studied in the prospective, nonrandomized, multicenter Carotid Revascularization With ev3 Inc. Arterial Technology Evolution (CREATE) trial of 419 patients with carotid artery disease who were at risk for stoke and at high risk for adverse events from surgery.

The risk of death, stroke, and MI at 30 days, or any stroke in the area of the blockage at 1 year, was similar to the rate of complications reported in the literature from patients undergoing surgery, according to the FDA. The study also showed that the stent still maintained blood flow to the brain more than 1 year after the procedure.

As part of the approval, the manufacturer, ev3, has agreed to conduct a long-term follow-up study of patients from the CREATE study to evaluate the effectiveness and safety of the stent through 3 years after its implantation, according to the FDA approval letter. This will include performing a clinical exam, carotid duplex ultrasound, and neurologic exam annually. The company also will conduct a postapproval study of at least 1,500 patients from high-, moderate-, and low-volume centers who were treated by physicians with different categories of training. The study will evaluate the composite rate of death, ipsilateral cerebrovascular accident (CVA), procedure-related CVA, or MI 30 days after the procedure in 1,000 patients. This study also will follow these patients and determine the rate of ipsilateral stroke at 12 months.

Plymouth, Minn.-based ev3 Inc. manufactures the stents and the distal filter embolic protection device. The filter is marketed as the SpiderRX Embolic Protection Device.

The Food and Drug Administration's latest approval of a carotid stent system came with a list of postmarketing study commitments that includes monitoring outcomes in recipients and evaluating training programs for physicians using the device.

In January, the FDA approved the Protégé GPS and Protégé RX carotid stent systems for treating patients with carotid artery disease who are at high risk for adverse events from carotid endarterectomy. The FDA requires use of the embolic protection devices made by the same company, approved by the FDA in February 2006, with the stent.

Candidates for the stent must meet the following criteria:

▸ They must have stenosis of the common or internal carotid artery measuring 50% or greater if they are symptomatic, or 80% or greater if they are asymptomatic (as determined by ultrasound or angiography).

▸ They must have a reference vessel diameter within the range of 4.5 mm and 9.5 mm at the target lesion.

The Protégé carotid stent system, with the embolic protection device, was studied in the prospective, nonrandomized, multicenter Carotid Revascularization With ev3 Inc. Arterial Technology Evolution (CREATE) trial of 419 patients with carotid artery disease who were at risk for stoke and at high risk for adverse events from surgery.

The risk of death, stroke, and MI at 30 days, or any stroke in the area of the blockage at 1 year, was similar to the rate of complications reported in the literature from patients undergoing surgery, according to the FDA. The study also showed that the stent still maintained blood flow to the brain more than 1 year after the procedure.

As part of the approval, the manufacturer, ev3, has agreed to conduct a long-term follow-up study of patients from the CREATE study to evaluate the effectiveness and safety of the stent through 3 years after its implantation, according to the FDA approval letter. This will include performing a clinical exam, carotid duplex ultrasound, and neurologic exam annually. The company also will conduct a postapproval study of at least 1,500 patients from high-, moderate-, and low-volume centers who were treated by physicians with different categories of training. The study will evaluate the composite rate of death, ipsilateral cerebrovascular accident (CVA), procedure-related CVA, or MI 30 days after the procedure in 1,000 patients. This study also will follow these patients and determine the rate of ipsilateral stroke at 12 months.

Plymouth, Minn.-based ev3 Inc. manufactures the stents and the distal filter embolic protection device. The filter is marketed as the SpiderRX Embolic Protection Device.

GAITHERSBURG, MD. — A federal advisory panel recommended against approval of an implantable device that continuously measures intracardiac pressures in ambulatory patients with moderate to advanced heart failure, but panel members were enthusiastic about its potential and urged the manufacturer to continue studying the device.

At a meeting last month, the Food and Drug Administration's Circulatory System Devices Panel voted 9–2 that the Chronicle Implantable Hemodynamic Monitoring (IHM) System was “nonapprovable.”

The manufacturer, Medtronic, had proposed that it be approved for the chronic management of patients with moderate to advanced heart failure in New York Heart Association class III or IV to reduce hospitalizations for worsening heart failure in these patients.

Although panelists generally agreed that intuitively, the technology made sense and provided useful information, they voted against approval because the COMPASS-HF study, the clinical trial submitted for approval, did not meet the primary effectiveness end point of showing that it reduced the rate of heart failure hospitalization equivalents (HF-related hospitalizations, HF-related emergency department or urgent-clinic visits requiring intravenous therapy) in patients with NYHA III or IV heart failure. And while the study provided reasonable assurance that the device was safe, panelists also cited the potential risks of an implantable device, with no effectiveness data to counterbalance the potential risks.

Panelist Dr. John Teerlink, director of heart failure at San Francisco Veterans Affairs Medical Center, described the technology as “tantalizing,” but said that there was no evidence that it reduced patient hospitalizations for worsening heart failure.

This is a “lifelong implant, with certain known risks” and unknown risks that may occur with time, said panelist Dr. Jeffrey Borer, head of the division of cardiovascular pathophysiology, at the New York-Presbyterian Hospital. While he believed that the device accurately measured pressures that he believed were physically and pathophysiologically relevant.

“I haven't seen the data that tell me how to apply this information for predictable clinical benefit,” Dr. Borer said.

The two panelists favoring approval thought that the device could be approved, but restricted to a very select population of heart failure patients.

The Chronicle IHM system includes the hemodynamic monitor, the size and shape of a pacemaker, that is implanted into the upper chest, with a pressure sensing lead that is inserted into the right ventricle.

The system measures and stores data on right ventricular systolic and diastolic pressures, and estimated pulmonary artery diastolic pressure, as well as heart rate, core temperature, and patient activity, information that is transmitted by the patient remotely to the clinician, who can access the data via a Web site.

The COMPASS HF multicenter study enrolled 274 patients with NYHA class III (84%–87% of the patients) or IV heart failure, whose mean age was 58, who had been on standard medical therapy for at least 3 months, and had at least one HF-related hospitalization or emergency department visit that required intravenous treatment within the previous 6 months. The device was implanted in all patients, but clinicians had no access to the information in 140 patients, who served as the controls.

The rate of heart failure hospitalization equivalents through 6 months, the primary effectiveness end point, was 21% lower in the Chronicle arm, which was not statistically significant: 44 patients in the Chronicle arm had 84 HF-related hospitalization equivalents, (an event rate of 0.67 over 6 months), compared with 60 patients in the control group who had 113 HF-related events, an event rate of 0.85. Events in both groups were mostly hospitalizations.

Clinicians made nearly three times as many adjustments of medications in the CHRONICLE patients, with no evidence of complications associated with overdiuresis, according to Medtronic.

The panel agreed there was reasonable assurance that the device was safe. Almost 92% of patients had no system-related complications over 6 months, and there were no cases of pressure sensor failures.

Of the 277 attempted implants (3 were not successful), there were 24 complications in 23 patients, most frequently lead dislodgement.

Panelists encouraged Medtronic to continue studying the device.

The FDA usually follows the recommendations of its expert advisory panels, which are not binding. In a statement issued after the meeting, Dr. David Steinhaus, medical director of cardiac disease management at Medtronic, said that the company was committed to making the Chronicle IHM available worldwide to heart failure patients and plans to work closely with the FDA to “define the appropriate path for approval.”

GAITHERSBURG, MD. — A federal advisory panel recommended against approval of an implantable device that continuously measures intracardiac pressures in ambulatory patients with moderate to advanced heart failure, but panel members were enthusiastic about its potential and urged the manufacturer to continue studying the device.

At a meeting last month, the Food and Drug Administration's Circulatory System Devices Panel voted 9–2 that the Chronicle Implantable Hemodynamic Monitoring (IHM) System was “nonapprovable.”

The manufacturer, Medtronic, had proposed that it be approved for the chronic management of patients with moderate to advanced heart failure in New York Heart Association class III or IV to reduce hospitalizations for worsening heart failure in these patients.

Although panelists generally agreed that intuitively, the technology made sense and provided useful information, they voted against approval because the COMPASS-HF study, the clinical trial submitted for approval, did not meet the primary effectiveness end point of showing that it reduced the rate of heart failure hospitalization equivalents (HF-related hospitalizations, HF-related emergency department or urgent-clinic visits requiring intravenous therapy) in patients with NYHA III or IV heart failure. And while the study provided reasonable assurance that the device was safe, panelists also cited the potential risks of an implantable device, with no effectiveness data to counterbalance the potential risks.

Panelist Dr. John Teerlink, director of heart failure at San Francisco Veterans Affairs Medical Center, described the technology as “tantalizing,” but said that there was no evidence that it reduced patient hospitalizations for worsening heart failure.

This is a “lifelong implant, with certain known risks” and unknown risks that may occur with time, said panelist Dr. Jeffrey Borer, head of the division of cardiovascular pathophysiology, at the New York-Presbyterian Hospital. While he believed that the device accurately measured pressures that he believed were physically and pathophysiologically relevant.

“I haven't seen the data that tell me how to apply this information for predictable clinical benefit,” Dr. Borer said.

The two panelists favoring approval thought that the device could be approved, but restricted to a very select population of heart failure patients.

The Chronicle IHM system includes the hemodynamic monitor, the size and shape of a pacemaker, that is implanted into the upper chest, with a pressure sensing lead that is inserted into the right ventricle.

The system measures and stores data on right ventricular systolic and diastolic pressures, and estimated pulmonary artery diastolic pressure, as well as heart rate, core temperature, and patient activity, information that is transmitted by the patient remotely to the clinician, who can access the data via a Web site.

The COMPASS HF multicenter study enrolled 274 patients with NYHA class III (84%–87% of the patients) or IV heart failure, whose mean age was 58, who had been on standard medical therapy for at least 3 months, and had at least one HF-related hospitalization or emergency department visit that required intravenous treatment within the previous 6 months. The device was implanted in all patients, but clinicians had no access to the information in 140 patients, who served as the controls.

The rate of heart failure hospitalization equivalents through 6 months, the primary effectiveness end point, was 21% lower in the Chronicle arm, which was not statistically significant: 44 patients in the Chronicle arm had 84 HF-related hospitalization equivalents, (an event rate of 0.67 over 6 months), compared with 60 patients in the control group who had 113 HF-related events, an event rate of 0.85. Events in both groups were mostly hospitalizations.

Clinicians made nearly three times as many adjustments of medications in the CHRONICLE patients, with no evidence of complications associated with overdiuresis, according to Medtronic.

The panel agreed there was reasonable assurance that the device was safe. Almost 92% of patients had no system-related complications over 6 months, and there were no cases of pressure sensor failures.

Of the 277 attempted implants (3 were not successful), there were 24 complications in 23 patients, most frequently lead dislodgement.

Panelists encouraged Medtronic to continue studying the device.

The FDA usually follows the recommendations of its expert advisory panels, which are not binding. In a statement issued after the meeting, Dr. David Steinhaus, medical director of cardiac disease management at Medtronic, said that the company was committed to making the Chronicle IHM available worldwide to heart failure patients and plans to work closely with the FDA to “define the appropriate path for approval.”

GAITHERSBURG, MD. — A federal advisory panel recommended against approval of an implantable device that continuously measures intracardiac pressures in ambulatory patients with moderate to advanced heart failure, but panel members were enthusiastic about its potential and urged the manufacturer to continue studying the device.

At a meeting last month, the Food and Drug Administration's Circulatory System Devices Panel voted 9–2 that the Chronicle Implantable Hemodynamic Monitoring (IHM) System was “nonapprovable.”

The manufacturer, Medtronic, had proposed that it be approved for the chronic management of patients with moderate to advanced heart failure in New York Heart Association class III or IV to reduce hospitalizations for worsening heart failure in these patients.

Although panelists generally agreed that intuitively, the technology made sense and provided useful information, they voted against approval because the COMPASS-HF study, the clinical trial submitted for approval, did not meet the primary effectiveness end point of showing that it reduced the rate of heart failure hospitalization equivalents (HF-related hospitalizations, HF-related emergency department or urgent-clinic visits requiring intravenous therapy) in patients with NYHA III or IV heart failure. And while the study provided reasonable assurance that the device was safe, panelists also cited the potential risks of an implantable device, with no effectiveness data to counterbalance the potential risks.

Panelist Dr. John Teerlink, director of heart failure at San Francisco Veterans Affairs Medical Center, described the technology as “tantalizing,” but said that there was no evidence that it reduced patient hospitalizations for worsening heart failure.

This is a “lifelong implant, with certain known risks” and unknown risks that may occur with time, said panelist Dr. Jeffrey Borer, head of the division of cardiovascular pathophysiology, at the New York-Presbyterian Hospital. While he believed that the device accurately measured pressures that he believed were physically and pathophysiologically relevant.

“I haven't seen the data that tell me how to apply this information for predictable clinical benefit,” Dr. Borer said.

The two panelists favoring approval thought that the device could be approved, but restricted to a very select population of heart failure patients.

The Chronicle IHM system includes the hemodynamic monitor, the size and shape of a pacemaker, that is implanted into the upper chest, with a pressure sensing lead that is inserted into the right ventricle.

The system measures and stores data on right ventricular systolic and diastolic pressures, and estimated pulmonary artery diastolic pressure, as well as heart rate, core temperature, and patient activity, information that is transmitted by the patient remotely to the clinician, who can access the data via a Web site.

The COMPASS HF multicenter study enrolled 274 patients with NYHA class III (84%–87% of the patients) or IV heart failure, whose mean age was 58, who had been on standard medical therapy for at least 3 months, and had at least one HF-related hospitalization or emergency department visit that required intravenous treatment within the previous 6 months. The device was implanted in all patients, but clinicians had no access to the information in 140 patients, who served as the controls.

The rate of heart failure hospitalization equivalents through 6 months, the primary effectiveness end point, was 21% lower in the Chronicle arm, which was not statistically significant: 44 patients in the Chronicle arm had 84 HF-related hospitalization equivalents, (an event rate of 0.67 over 6 months), compared with 60 patients in the control group who had 113 HF-related events, an event rate of 0.85. Events in both groups were mostly hospitalizations.

Clinicians made nearly three times as many adjustments of medications in the CHRONICLE patients, with no evidence of complications associated with overdiuresis, according to Medtronic.

The panel agreed there was reasonable assurance that the device was safe. Almost 92% of patients had no system-related complications over 6 months, and there were no cases of pressure sensor failures.

Of the 277 attempted implants (3 were not successful), there were 24 complications in 23 patients, most frequently lead dislodgement.

Panelists encouraged Medtronic to continue studying the device.

The FDA usually follows the recommendations of its expert advisory panels, which are not binding. In a statement issued after the meeting, Dr. David Steinhaus, medical director of cardiac disease management at Medtronic, said that the company was committed to making the Chronicle IHM available worldwide to heart failure patients and plans to work closely with the FDA to “define the appropriate path for approval.”

GAITHERSBURG, MD. — An inactivated H5N1 influenza virus vaccine that a federal advisory panel has recommended for approval would, if approved, become the first vaccine for avian influenza licensed in the United States.

At a meeting of the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee, the panel agreed that that there were sufficient data to support the safety and effectiveness of the investigational vaccine during an avian flu pandemic or in situations of potential high-risk exposure. The vaccine is based on an A/Vietnam strain of the H5N1 avian influenza virus.

The proposed indication for the vaccine, manufactured by Sanofi Pasteur, is for active immunization against influenza disease caused by the H5N1 A/Vietnam/1203/2004 influenza virus and for primary vaccination of healthy adults aged 18–64. Two 90-mcg doses of the vaccine would be administered intramuscularly, 28 days apart.

If approved, the vaccine would not be available commercially but would be part of the prepandemic vaccine stockpile in the United States.

This “is an important step in the development of a pandemic influenza vaccine,” said panel chair Dr. Ruth A. Karron, professor in the department of international health, Johns Hopkins School of Hygiene and Public Health, Baltimore.

Throughout the meeting, panelists and FDA officials referred to the vaccine as an “interim” or “stopgap” vaccine. Many other vaccines are being developed that are potentially better than this vaccine, said Dr. Norman Baylor, director of the FDA's office of vaccines research and review.

Panelist Robert Webster, Ph.D., chair of the department of virology and molecular biology at St. Jude Children's Research Hospital, Memphis, said it would not be clear how well the current vaccine works unless it were used in an actual pandemic. Nevertheless, if the H5N1 influenza virus does acquire human-to-human transmissibility, there will not be enough time to produce enough vaccine, so “we need this stockpile,” he said.

The vaccine is manufactured with the same process used for the seasonal influenza virus vaccine, which several panel members said provided reassurance about its safety.

The vaccine contains a much higher amount of antigen than the seasonal flu vaccine, however, which raised some concerns about the potential for adverse effects.

Safety and efficacy data came from a prospective, multicenter randomized double-blind phase I/II trial launched in 2004 and conducted by the National Institute of Allergy and Infectious Diseases. Investigators measured hemagglutinin inhibition (HAI) immunogenicity in 452 adults, aged 18–64, who received two injections of different vaccine doses 28 days apart.

The response rate—at least a fourfold increase in the HAI titer 28 days after the injection—among those who received the 90-mcg dose was 23% after the first dose and 45% after the second dose, with a waning of the response rate to about 18% 6 months after the second dose, said Dr. Andrea James of the FDA's division of vaccines and related product applications.

The immunogenicity in this study is less than that usually seen in studies of seasonal influenza vaccine, she pointed out.

Dose-related injection site reactions were the most common side effects, with 85% of those receiving 90-mcg doses having at least one such reaction. Systemic events were less frequent, with about 40% developing headache and 30% developing malaise with the 90-mcg dose, Dr. James said.

The vaccine is also being investigated in a study of 259 elderly adults and a study of 125 children aged 2–9. Once the FDA makes a decision about licensing of the vaccine for people ages 18–64, the company will initiate discussions about expanding the age range for approval, according to Sanofi Pasteur.

GAITHERSBURG, MD. — An inactivated H5N1 influenza virus vaccine that a federal advisory panel has recommended for approval would, if approved, become the first vaccine for avian influenza licensed in the United States.

At a meeting of the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee, the panel agreed that that there were sufficient data to support the safety and effectiveness of the investigational vaccine during an avian flu pandemic or in situations of potential high-risk exposure. The vaccine is based on an A/Vietnam strain of the H5N1 avian influenza virus.

The proposed indication for the vaccine, manufactured by Sanofi Pasteur, is for active immunization against influenza disease caused by the H5N1 A/Vietnam/1203/2004 influenza virus and for primary vaccination of healthy adults aged 18–64. Two 90-mcg doses of the vaccine would be administered intramuscularly, 28 days apart.

If approved, the vaccine would not be available commercially but would be part of the prepandemic vaccine stockpile in the United States.

This “is an important step in the development of a pandemic influenza vaccine,” said panel chair Dr. Ruth A. Karron, professor in the department of international health, Johns Hopkins School of Hygiene and Public Health, Baltimore.

Throughout the meeting, panelists and FDA officials referred to the vaccine as an “interim” or “stopgap” vaccine. Many other vaccines are being developed that are potentially better than this vaccine, said Dr. Norman Baylor, director of the FDA's office of vaccines research and review.

Panelist Robert Webster, Ph.D., chair of the department of virology and molecular biology at St. Jude Children's Research Hospital, Memphis, said it would not be clear how well the current vaccine works unless it were used in an actual pandemic. Nevertheless, if the H5N1 influenza virus does acquire human-to-human transmissibility, there will not be enough time to produce enough vaccine, so “we need this stockpile,” he said.

The vaccine is manufactured with the same process used for the seasonal influenza virus vaccine, which several panel members said provided reassurance about its safety.

The vaccine contains a much higher amount of antigen than the seasonal flu vaccine, however, which raised some concerns about the potential for adverse effects.

Safety and efficacy data came from a prospective, multicenter randomized double-blind phase I/II trial launched in 2004 and conducted by the National Institute of Allergy and Infectious Diseases. Investigators measured hemagglutinin inhibition (HAI) immunogenicity in 452 adults, aged 18–64, who received two injections of different vaccine doses 28 days apart.

The response rate—at least a fourfold increase in the HAI titer 28 days after the injection—among those who received the 90-mcg dose was 23% after the first dose and 45% after the second dose, with a waning of the response rate to about 18% 6 months after the second dose, said Dr. Andrea James of the FDA's division of vaccines and related product applications.

The immunogenicity in this study is less than that usually seen in studies of seasonal influenza vaccine, she pointed out.

Dose-related injection site reactions were the most common side effects, with 85% of those receiving 90-mcg doses having at least one such reaction. Systemic events were less frequent, with about 40% developing headache and 30% developing malaise with the 90-mcg dose, Dr. James said.

The vaccine is also being investigated in a study of 259 elderly adults and a study of 125 children aged 2–9. Once the FDA makes a decision about licensing of the vaccine for people ages 18–64, the company will initiate discussions about expanding the age range for approval, according to Sanofi Pasteur.

GAITHERSBURG, MD. — An inactivated H5N1 influenza virus vaccine that a federal advisory panel has recommended for approval would, if approved, become the first vaccine for avian influenza licensed in the United States.

At a meeting of the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee, the panel agreed that that there were sufficient data to support the safety and effectiveness of the investigational vaccine during an avian flu pandemic or in situations of potential high-risk exposure. The vaccine is based on an A/Vietnam strain of the H5N1 avian influenza virus.

The proposed indication for the vaccine, manufactured by Sanofi Pasteur, is for active immunization against influenza disease caused by the H5N1 A/Vietnam/1203/2004 influenza virus and for primary vaccination of healthy adults aged 18–64. Two 90-mcg doses of the vaccine would be administered intramuscularly, 28 days apart.

If approved, the vaccine would not be available commercially but would be part of the prepandemic vaccine stockpile in the United States.

This “is an important step in the development of a pandemic influenza vaccine,” said panel chair Dr. Ruth A. Karron, professor in the department of international health, Johns Hopkins School of Hygiene and Public Health, Baltimore.

Throughout the meeting, panelists and FDA officials referred to the vaccine as an “interim” or “stopgap” vaccine. Many other vaccines are being developed that are potentially better than this vaccine, said Dr. Norman Baylor, director of the FDA's office of vaccines research and review.

Panelist Robert Webster, Ph.D., chair of the department of virology and molecular biology at St. Jude Children's Research Hospital, Memphis, said it would not be clear how well the current vaccine works unless it were used in an actual pandemic. Nevertheless, if the H5N1 influenza virus does acquire human-to-human transmissibility, there will not be enough time to produce enough vaccine, so “we need this stockpile,” he said.

The vaccine is manufactured with the same process used for the seasonal influenza virus vaccine, which several panel members said provided reassurance about its safety.

The vaccine contains a much higher amount of antigen than the seasonal flu vaccine, however, which raised some concerns about the potential for adverse effects.

Safety and efficacy data came from a prospective, multicenter randomized double-blind phase I/II trial launched in 2004 and conducted by the National Institute of Allergy and Infectious Diseases. Investigators measured hemagglutinin inhibition (HAI) immunogenicity in 452 adults, aged 18–64, who received two injections of different vaccine doses 28 days apart.

The response rate—at least a fourfold increase in the HAI titer 28 days after the injection—among those who received the 90-mcg dose was 23% after the first dose and 45% after the second dose, with a waning of the response rate to about 18% 6 months after the second dose, said Dr. Andrea James of the FDA's division of vaccines and related product applications.

The immunogenicity in this study is less than that usually seen in studies of seasonal influenza vaccine, she pointed out.

Dose-related injection site reactions were the most common side effects, with 85% of those receiving 90-mcg doses having at least one such reaction. Systemic events were less frequent, with about 40% developing headache and 30% developing malaise with the 90-mcg dose, Dr. James said.

The vaccine is also being investigated in a study of 259 elderly adults and a study of 125 children aged 2–9. Once the FDA makes a decision about licensing of the vaccine for people ages 18–64, the company will initiate discussions about expanding the age range for approval, according to Sanofi Pasteur.

Warnings about the risks of complex sleep-related behaviors such as driving while asleep and about serious allergic reactions that have recently been associated with sleep drugs, are being added to their labels, at the request of the Food and Drug Administration.

The FDA announced that the manufacturers of the 13 approved sedative hypnotics, which include older drugs such as Dalmane and newer drugs such as Ambien and Lunesta, had been asked to describe cases of anaphylaxis and angioedema, and cases of complex sleep-related behaviors in their labels. In addition, the drugmakers have begun sending out “Dear Health Care Provider” letters describing these adverse events and the label changes.

The need for these changes are based on postmarketing reports of these events, “which we believe are serious and about which practitioners and patients need to know,” Dr. Russell Katz, director of the FDA's division of neurology products, said during an FDA teleconference.

After receiving postmarketing reports of angioedema and anaphylaxis in people on the most recently approved hypnotic, ramelteon (Rozerem), the FDA reviewed the entire class for this effect and found similar cases. The review of complex sleep-related behaviors—which include driving, making phone calls, preparing and eating food, and having sex, all while asleep—began after such cases were publicized about 1 year ago. Although such cases can be difficult to interpret, “we believe the entire class is capable of producing those events as well,” Dr. Katz said. Physicians should advise patients that the complex sleep behaviors are more likely to occur when people take higher than normal doses, and when they take these drugs with other drugs that can affect the nervous system or with alcohol, he added.

Dr. Katz described both types of events as “relatively rare,” based on the information available. He added that no deaths have been reported in association with any of the events reported to the FDA.

After the teleconference, an FDA spokesperson said that the agency had received a “couple of dozen” reports of complex sleep behaviors but emphasized that these events are likely to be underreported, and that the decision to strengthen labeling was not based on numbers but on the serious nature of these adverse effects. There were more cases of allergic reactions, but no specific numbers were provided.

Manufacturers also have been asked to develop “Patient Medication Guides” to directly inform patients about the risks and about what they can do to minimize their risks of experiencing these events. Medication guides are leaflets that are required for certain drugs with particular risks, which are distributed with each new prescription or refill. These will not be available soon, however, since the companies have until May to submit their versions of the guides, which will then need to be reviewed by the agency.

But the events also are being added to the “information for patients” section of the drug labels, which physicians can use to counsel patients. “Patients should be aware that there are behaviors that they can engage in that can decrease the risk of these events occurring, namely, to refrain from alcohol [and] other drugs that depress the nervous system and to make sure they take the right dose,” Dr. Katz emphasized.

The FDA also has requested that the manufacturers conduct clinical trials to determine whether the complex sleep behaviors are more common with some of the drugs and not others. Dr. Katz said that none of the companies had approached the agency yet with plans for such studies and acknowledged that getting them to do studies would be more difficult than making the labeling changes.

The label change affects drugs including Zolpidem, marketed as Ambien/Ambien CR by Sanofi-Aventis; butabarbital, marketed as Butisol Sodium by Medpointe Pharmaceuticals HLC; flurazepam, marketed as Dalmane by Valeant Pharmaceuticals; quazepam, marketed as Doral by Questcor Pharmaceuticals; triazolam, marketed as Halcion by Pharmacia & Upjohn Inc.; eszopiclone, marketed as Lunesta by Sepracor Inc.; estazolam, marketed as Prosom by Abbott; temazepam, marketed as Restoril by Tyco Healthcare Group; ramelteon, marketed as Rozerem by Takeda Pharmaceutical Inc.; secobarbital, marketed as Seconal by Ranbaxy Pharmaceuticals Inc.; and zaleplon, marketed as Sonata by King Pharmaceuticals Inc.

Health care professionals can report serious adverse reactions to these and other drugs to the FDA's Medwatch program online at www.fda.gov/medwatch

Warnings about the risks of complex sleep-related behaviors such as driving while asleep and about serious allergic reactions that have recently been associated with sleep drugs, are being added to their labels, at the request of the Food and Drug Administration.

The FDA announced that the manufacturers of the 13 approved sedative hypnotics, which include older drugs such as Dalmane and newer drugs such as Ambien and Lunesta, had been asked to describe cases of anaphylaxis and angioedema, and cases of complex sleep-related behaviors in their labels. In addition, the drugmakers have begun sending out “Dear Health Care Provider” letters describing these adverse events and the label changes.

The need for these changes are based on postmarketing reports of these events, “which we believe are serious and about which practitioners and patients need to know,” Dr. Russell Katz, director of the FDA's division of neurology products, said during an FDA teleconference.

After receiving postmarketing reports of angioedema and anaphylaxis in people on the most recently approved hypnotic, ramelteon (Rozerem), the FDA reviewed the entire class for this effect and found similar cases. The review of complex sleep-related behaviors—which include driving, making phone calls, preparing and eating food, and having sex, all while asleep—began after such cases were publicized about 1 year ago. Although such cases can be difficult to interpret, “we believe the entire class is capable of producing those events as well,” Dr. Katz said. Physicians should advise patients that the complex sleep behaviors are more likely to occur when people take higher than normal doses, and when they take these drugs with other drugs that can affect the nervous system or with alcohol, he added.

Dr. Katz described both types of events as “relatively rare,” based on the information available. He added that no deaths have been reported in association with any of the events reported to the FDA.

After the teleconference, an FDA spokesperson said that the agency had received a “couple of dozen” reports of complex sleep behaviors but emphasized that these events are likely to be underreported, and that the decision to strengthen labeling was not based on numbers but on the serious nature of these adverse effects. There were more cases of allergic reactions, but no specific numbers were provided.

Manufacturers also have been asked to develop “Patient Medication Guides” to directly inform patients about the risks and about what they can do to minimize their risks of experiencing these events. Medication guides are leaflets that are required for certain drugs with particular risks, which are distributed with each new prescription or refill. These will not be available soon, however, since the companies have until May to submit their versions of the guides, which will then need to be reviewed by the agency.

But the events also are being added to the “information for patients” section of the drug labels, which physicians can use to counsel patients. “Patients should be aware that there are behaviors that they can engage in that can decrease the risk of these events occurring, namely, to refrain from alcohol [and] other drugs that depress the nervous system and to make sure they take the right dose,” Dr. Katz emphasized.

The FDA also has requested that the manufacturers conduct clinical trials to determine whether the complex sleep behaviors are more common with some of the drugs and not others. Dr. Katz said that none of the companies had approached the agency yet with plans for such studies and acknowledged that getting them to do studies would be more difficult than making the labeling changes.

The label change affects drugs including Zolpidem, marketed as Ambien/Ambien CR by Sanofi-Aventis; butabarbital, marketed as Butisol Sodium by Medpointe Pharmaceuticals HLC; flurazepam, marketed as Dalmane by Valeant Pharmaceuticals; quazepam, marketed as Doral by Questcor Pharmaceuticals; triazolam, marketed as Halcion by Pharmacia & Upjohn Inc.; eszopiclone, marketed as Lunesta by Sepracor Inc.; estazolam, marketed as Prosom by Abbott; temazepam, marketed as Restoril by Tyco Healthcare Group; ramelteon, marketed as Rozerem by Takeda Pharmaceutical Inc.; secobarbital, marketed as Seconal by Ranbaxy Pharmaceuticals Inc.; and zaleplon, marketed as Sonata by King Pharmaceuticals Inc.

Health care professionals can report serious adverse reactions to these and other drugs to the FDA's Medwatch program online at www.fda.gov/medwatch

Warnings about the risks of complex sleep-related behaviors such as driving while asleep and about serious allergic reactions that have recently been associated with sleep drugs, are being added to their labels, at the request of the Food and Drug Administration.

The FDA announced that the manufacturers of the 13 approved sedative hypnotics, which include older drugs such as Dalmane and newer drugs such as Ambien and Lunesta, had been asked to describe cases of anaphylaxis and angioedema, and cases of complex sleep-related behaviors in their labels. In addition, the drugmakers have begun sending out “Dear Health Care Provider” letters describing these adverse events and the label changes.

The need for these changes are based on postmarketing reports of these events, “which we believe are serious and about which practitioners and patients need to know,” Dr. Russell Katz, director of the FDA's division of neurology products, said during an FDA teleconference.

After receiving postmarketing reports of angioedema and anaphylaxis in people on the most recently approved hypnotic, ramelteon (Rozerem), the FDA reviewed the entire class for this effect and found similar cases. The review of complex sleep-related behaviors—which include driving, making phone calls, preparing and eating food, and having sex, all while asleep—began after such cases were publicized about 1 year ago. Although such cases can be difficult to interpret, “we believe the entire class is capable of producing those events as well,” Dr. Katz said. Physicians should advise patients that the complex sleep behaviors are more likely to occur when people take higher than normal doses, and when they take these drugs with other drugs that can affect the nervous system or with alcohol, he added.

Dr. Katz described both types of events as “relatively rare,” based on the information available. He added that no deaths have been reported in association with any of the events reported to the FDA.

After the teleconference, an FDA spokesperson said that the agency had received a “couple of dozen” reports of complex sleep behaviors but emphasized that these events are likely to be underreported, and that the decision to strengthen labeling was not based on numbers but on the serious nature of these adverse effects. There were more cases of allergic reactions, but no specific numbers were provided.

Manufacturers also have been asked to develop “Patient Medication Guides” to directly inform patients about the risks and about what they can do to minimize their risks of experiencing these events. Medication guides are leaflets that are required for certain drugs with particular risks, which are distributed with each new prescription or refill. These will not be available soon, however, since the companies have until May to submit their versions of the guides, which will then need to be reviewed by the agency.

But the events also are being added to the “information for patients” section of the drug labels, which physicians can use to counsel patients. “Patients should be aware that there are behaviors that they can engage in that can decrease the risk of these events occurring, namely, to refrain from alcohol [and] other drugs that depress the nervous system and to make sure they take the right dose,” Dr. Katz emphasized.

The FDA also has requested that the manufacturers conduct clinical trials to determine whether the complex sleep behaviors are more common with some of the drugs and not others. Dr. Katz said that none of the companies had approached the agency yet with plans for such studies and acknowledged that getting them to do studies would be more difficult than making the labeling changes.

The label change affects drugs including Zolpidem, marketed as Ambien/Ambien CR by Sanofi-Aventis; butabarbital, marketed as Butisol Sodium by Medpointe Pharmaceuticals HLC; flurazepam, marketed as Dalmane by Valeant Pharmaceuticals; quazepam, marketed as Doral by Questcor Pharmaceuticals; triazolam, marketed as Halcion by Pharmacia & Upjohn Inc.; eszopiclone, marketed as Lunesta by Sepracor Inc.; estazolam, marketed as Prosom by Abbott; temazepam, marketed as Restoril by Tyco Healthcare Group; ramelteon, marketed as Rozerem by Takeda Pharmaceutical Inc.; secobarbital, marketed as Seconal by Ranbaxy Pharmaceuticals Inc.; and zaleplon, marketed as Sonata by King Pharmaceuticals Inc.

Health care professionals can report serious adverse reactions to these and other drugs to the FDA's Medwatch program online at www.fda.gov/medwatch

ROCKVILLE, MD. — More than 11,000 perioperative medication errors were reported to a national database of hospital medication errors between 1998 and 2005. Of these, 5% resulted in harm, according to a report issued by the United States Pharmacopeia.

The database, known as MEDMARX, is operated by the USP and is the largest national database of hospital medication errors in the United States, receiving about 15,000 new reports every month.

The 11,239 perioperative medication errors reported by more than 500 hospitals in 7 years were divided into four settings: outpatient surgery (30% of the total reports), the preoperative holding area (7%), the operating room (34%), and the postanesthesia care unit (29%). The proportion reported in the preoperative holding area was lower because this category was added to the database in 2003.

The 5% rate of harmful perioperative errors is about threefold higher than the proportion of medication errors resulting in harm in all other areas of the hospital combined. Harmful errors occurred in all four perioperative areas but were most common in the operating room. The proportion of perioperative medication errors that resulted in harm was higher among patients under age 17 than it was among older patients.

Among the medication errors that resulted in harm, there were four deaths, including one pediatric patient, according to Diane D. Cousins, a registered pharmacist and vice president of the Center for the Advancement of Patient Safety at the USP.

A total of 739 drug products were involved in errors, the most common of which were the antibiotics cefazolin and vancomycin; the analgesics morphine, fentanyl, and meperidine; the sedative midazolam; and heparin, Ms. Cousins said. There were 165 drugs (22%) involved in harmful errors; most common among them were morphine, fentanyl, and cefazolin.

Errors included administering the wrong medication or the wrong amount, administering medication at the wrong time, omitting a medication or a dose, or administering medication incorrectly.

In the operating room, omission and wrong drug administration were the most common mistakes, she said. For example, a surgeon called in an order for a dose of ampicillin to be given during surgery that was scheduled a week later, but the order was never recorded. As a result, the patient (a child) never received the drug.

In the postanesthesia care unit setting, the most typical errors involved prescribing and administering incorrect amounts of drugs, she said. After an elderly patient was discharged from the postanesthesia care unit to an inpatient unit, it was discovered that the patient was receiving too much heparin because of a programming error made in the postanesthesia care unit.

The results were announced during a press briefing sponsored by the USP, which released the report in partnership with the Uniformed Services University of the Health Sciences, the Association of PeriOperative Registered Nurses, and the American Society of PeriAnesthesia Nurses. The report is the largest known national analysis of medication errors related to surgery, Ms. Cousins said during the press conference.

ROCKVILLE, MD. — More than 11,000 perioperative medication errors were reported to a national database of hospital medication errors between 1998 and 2005. Of these, 5% resulted in harm, according to a report issued by the United States Pharmacopeia.

The database, known as MEDMARX, is operated by the USP and is the largest national database of hospital medication errors in the United States, receiving about 15,000 new reports every month.

The 11,239 perioperative medication errors reported by more than 500 hospitals in 7 years were divided into four settings: outpatient surgery (30% of the total reports), the preoperative holding area (7%), the operating room (34%), and the postanesthesia care unit (29%). The proportion reported in the preoperative holding area was lower because this category was added to the database in 2003.

The 5% rate of harmful perioperative errors is about threefold higher than the proportion of medication errors resulting in harm in all other areas of the hospital combined. Harmful errors occurred in all four perioperative areas but were most common in the operating room. The proportion of perioperative medication errors that resulted in harm was higher among patients under age 17 than it was among older patients.

Among the medication errors that resulted in harm, there were four deaths, including one pediatric patient, according to Diane D. Cousins, a registered pharmacist and vice president of the Center for the Advancement of Patient Safety at the USP.

A total of 739 drug products were involved in errors, the most common of which were the antibiotics cefazolin and vancomycin; the analgesics morphine, fentanyl, and meperidine; the sedative midazolam; and heparin, Ms. Cousins said. There were 165 drugs (22%) involved in harmful errors; most common among them were morphine, fentanyl, and cefazolin.

Errors included administering the wrong medication or the wrong amount, administering medication at the wrong time, omitting a medication or a dose, or administering medication incorrectly.

In the operating room, omission and wrong drug administration were the most common mistakes, she said. For example, a surgeon called in an order for a dose of ampicillin to be given during surgery that was scheduled a week later, but the order was never recorded. As a result, the patient (a child) never received the drug.

In the postanesthesia care unit setting, the most typical errors involved prescribing and administering incorrect amounts of drugs, she said. After an elderly patient was discharged from the postanesthesia care unit to an inpatient unit, it was discovered that the patient was receiving too much heparin because of a programming error made in the postanesthesia care unit.

The results were announced during a press briefing sponsored by the USP, which released the report in partnership with the Uniformed Services University of the Health Sciences, the Association of PeriOperative Registered Nurses, and the American Society of PeriAnesthesia Nurses. The report is the largest known national analysis of medication errors related to surgery, Ms. Cousins said during the press conference.

ROCKVILLE, MD. — More than 11,000 perioperative medication errors were reported to a national database of hospital medication errors between 1998 and 2005. Of these, 5% resulted in harm, according to a report issued by the United States Pharmacopeia.

The database, known as MEDMARX, is operated by the USP and is the largest national database of hospital medication errors in the United States, receiving about 15,000 new reports every month.

The 11,239 perioperative medication errors reported by more than 500 hospitals in 7 years were divided into four settings: outpatient surgery (30% of the total reports), the preoperative holding area (7%), the operating room (34%), and the postanesthesia care unit (29%). The proportion reported in the preoperative holding area was lower because this category was added to the database in 2003.

The 5% rate of harmful perioperative errors is about threefold higher than the proportion of medication errors resulting in harm in all other areas of the hospital combined. Harmful errors occurred in all four perioperative areas but were most common in the operating room. The proportion of perioperative medication errors that resulted in harm was higher among patients under age 17 than it was among older patients.

Among the medication errors that resulted in harm, there were four deaths, including one pediatric patient, according to Diane D. Cousins, a registered pharmacist and vice president of the Center for the Advancement of Patient Safety at the USP.

A total of 739 drug products were involved in errors, the most common of which were the antibiotics cefazolin and vancomycin; the analgesics morphine, fentanyl, and meperidine; the sedative midazolam; and heparin, Ms. Cousins said. There were 165 drugs (22%) involved in harmful errors; most common among them were morphine, fentanyl, and cefazolin.

Errors included administering the wrong medication or the wrong amount, administering medication at the wrong time, omitting a medication or a dose, or administering medication incorrectly.

In the operating room, omission and wrong drug administration were the most common mistakes, she said. For example, a surgeon called in an order for a dose of ampicillin to be given during surgery that was scheduled a week later, but the order was never recorded. As a result, the patient (a child) never received the drug.

In the postanesthesia care unit setting, the most typical errors involved prescribing and administering incorrect amounts of drugs, she said. After an elderly patient was discharged from the postanesthesia care unit to an inpatient unit, it was discovered that the patient was receiving too much heparin because of a programming error made in the postanesthesia care unit.

The results were announced during a press briefing sponsored by the USP, which released the report in partnership with the Uniformed Services University of the Health Sciences, the Association of PeriOperative Registered Nurses, and the American Society of PeriAnesthesia Nurses. The report is the largest known national analysis of medication errors related to surgery, Ms. Cousins said during the press conference.