Elizabeth Mechcatie

The first generic formulations of the beta-blocker carvedilol (Coreg) have been approvedby the Food and Drug Administration for treating hypertension, mild to severe chronic heart failure, and left ventricular dysfunction following a myocardial infarction in clinically stable patients.

Available in four strengths—3.125 mg, 6.25 mg, 12.5 mg, and 25 mg—the tablets are made by these companies: Actavis Elizabeth LLC, Apotex Inc., Aurobindo Pharma Ltd., Caraco Pharmaceutical Laboratories Ltd., Dr. Reddy's Laboratories Ltd., Glenmark Pharmaceuticals Ltd., Lupin Ltd., Mylan Pharmaceuticals Inc., Ranbaxy Laboratories Ltd., Sandoz Inc., Taro Pharmaceutical Industries Ltd., TEVA Pharmaceuticals USA, Watson Laboratories Inc., and Zydus Pharmaceuticals (USA) Inc.

The first generic formulations of the beta-blocker carvedilol (Coreg) have been approvedby the Food and Drug Administration for treating hypertension, mild to severe chronic heart failure, and left ventricular dysfunction following a myocardial infarction in clinically stable patients.

Available in four strengths—3.125 mg, 6.25 mg, 12.5 mg, and 25 mg—the tablets are made by these companies: Actavis Elizabeth LLC, Apotex Inc., Aurobindo Pharma Ltd., Caraco Pharmaceutical Laboratories Ltd., Dr. Reddy's Laboratories Ltd., Glenmark Pharmaceuticals Ltd., Lupin Ltd., Mylan Pharmaceuticals Inc., Ranbaxy Laboratories Ltd., Sandoz Inc., Taro Pharmaceutical Industries Ltd., TEVA Pharmaceuticals USA, Watson Laboratories Inc., and Zydus Pharmaceuticals (USA) Inc.

The first generic formulations of the beta-blocker carvedilol (Coreg) have been approvedby the Food and Drug Administration for treating hypertension, mild to severe chronic heart failure, and left ventricular dysfunction following a myocardial infarction in clinically stable patients.

Available in four strengths—3.125 mg, 6.25 mg, 12.5 mg, and 25 mg—the tablets are made by these companies: Actavis Elizabeth LLC, Apotex Inc., Aurobindo Pharma Ltd., Caraco Pharmaceutical Laboratories Ltd., Dr. Reddy's Laboratories Ltd., Glenmark Pharmaceuticals Ltd., Lupin Ltd., Mylan Pharmaceuticals Inc., Ranbaxy Laboratories Ltd., Sandoz Inc., Taro Pharmaceutical Industries Ltd., TEVA Pharmaceuticals USA, Watson Laboratories Inc., and Zydus Pharmaceuticals (USA) Inc.

A sustained-release formulation of the somatostatin analogue lanreotide has been approved by the Food and Drug Administration for the long-term treatment of acromegaly patients who have had an inadequate response to or cannot be treated with surgery or radiotherapy.

Lanreotide is administered via a deep subcutaneous injection every 4 weeks for 3 months, after which time the dosage is adjusted based on the patient's response, which is determined by a reduction in serum growth hormone or insulin growth factor-1 (IGF-1) levels, as well as changes in symptoms of acromegaly, according to the labeling.

In the United States, the prolonged-release formulation of lanreotide, which the label says is a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin, is being marketed as Somatuline Depot.

The label cites two long-term, randomized multicenter studies of different doses of Somatuline Depot in patients with acromegaly. In a 1-year study, 108 patients with active acromegaly were randomized to receive a 60-mg, 90-mg, or 120-mg injection of lanreotide or placebo, after which all patients received a fixed dose every 4 weeks for 4 months (4 injections), followed by a dose-titration phase of 8 injections for a total of 13 injections over 12 months. At the end of the first month, 63% of the patients treated with lanreotide had more than a 50% drop in mean growth hormone (GH) levels from baseline, compared with none of the 25 patients on placebo. At week 16, the end of the fixed dose phase, 72% of the lanreotide-treated patients had more than a 50% reduction in mean GH level, which was maintained for the rest of the study.

The second study described in the label was a 48-week, open-label, uncontrolled study of 63 patients with an IGF-1 level that was at least 1.3 times the upper limit of the age-adjusted normal range. During a 4-month fixed-dose phase, patients received four injections of 90 mg of Somatuline Depot every 4 weeks. This was followed by a dose-titration phase, during which the dose was adjusted based on GH and IGF-1 levels at the beginning of this phase, and again, if needed, after patients received another four injections. After 48 weeks, 43% of the patients achieved a normal age-adjusted IGF-1 concentration. The mean IGF-1 concentration after treatment was 1.3 ± 0.7 times the upper limit of normal, compared with 2.5 ± the upper limit of normal at baseline. The drop in IGF-1 levels “over time correlated with a corresponding marked decrease in GH concentrations,” according to the label, which cited the most common adverse reactions associated with treatment as diarrhea, cholelithiasis, abdominal pain, nausea, and injection site reactions.

Somatuline Depot, which has been available in Europe for a while, will be “a useful addition to our formularies,” Dr. Rhoda H. Cobin of Mount Sinai School of Medicine, New York, said in an interview. It is a longer-acting version of octreotide, used in the United States, which makes administration easier and will help with patient compliance, said Dr. Cobin, the immediate past president of the American College of Endocrinology and past president of the American Association of Clinical Endocrinologists.

Somatuline Depot is manufactured by Ipsen. Tercica, has the U.S. distribution rights and expects to launch the drug in the fourth quarter of 2007, according to Ipsen.

It is a longer-acting version of octreotide, making its administration easier and helping with patient compliance. DR. COBIN

A sustained-release formulation of the somatostatin analogue lanreotide has been approved by the Food and Drug Administration for the long-term treatment of acromegaly patients who have had an inadequate response to or cannot be treated with surgery or radiotherapy.

Lanreotide is administered via a deep subcutaneous injection every 4 weeks for 3 months, after which time the dosage is adjusted based on the patient's response, which is determined by a reduction in serum growth hormone or insulin growth factor-1 (IGF-1) levels, as well as changes in symptoms of acromegaly, according to the labeling.

In the United States, the prolonged-release formulation of lanreotide, which the label says is a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin, is being marketed as Somatuline Depot.

The label cites two long-term, randomized multicenter studies of different doses of Somatuline Depot in patients with acromegaly. In a 1-year study, 108 patients with active acromegaly were randomized to receive a 60-mg, 90-mg, or 120-mg injection of lanreotide or placebo, after which all patients received a fixed dose every 4 weeks for 4 months (4 injections), followed by a dose-titration phase of 8 injections for a total of 13 injections over 12 months. At the end of the first month, 63% of the patients treated with lanreotide had more than a 50% drop in mean growth hormone (GH) levels from baseline, compared with none of the 25 patients on placebo. At week 16, the end of the fixed dose phase, 72% of the lanreotide-treated patients had more than a 50% reduction in mean GH level, which was maintained for the rest of the study.

The second study described in the label was a 48-week, open-label, uncontrolled study of 63 patients with an IGF-1 level that was at least 1.3 times the upper limit of the age-adjusted normal range. During a 4-month fixed-dose phase, patients received four injections of 90 mg of Somatuline Depot every 4 weeks. This was followed by a dose-titration phase, during which the dose was adjusted based on GH and IGF-1 levels at the beginning of this phase, and again, if needed, after patients received another four injections. After 48 weeks, 43% of the patients achieved a normal age-adjusted IGF-1 concentration. The mean IGF-1 concentration after treatment was 1.3 ± 0.7 times the upper limit of normal, compared with 2.5 ± the upper limit of normal at baseline. The drop in IGF-1 levels “over time correlated with a corresponding marked decrease in GH concentrations,” according to the label, which cited the most common adverse reactions associated with treatment as diarrhea, cholelithiasis, abdominal pain, nausea, and injection site reactions.

Somatuline Depot, which has been available in Europe for a while, will be “a useful addition to our formularies,” Dr. Rhoda H. Cobin of Mount Sinai School of Medicine, New York, said in an interview. It is a longer-acting version of octreotide, used in the United States, which makes administration easier and will help with patient compliance, said Dr. Cobin, the immediate past president of the American College of Endocrinology and past president of the American Association of Clinical Endocrinologists.

Somatuline Depot is manufactured by Ipsen. Tercica, has the U.S. distribution rights and expects to launch the drug in the fourth quarter of 2007, according to Ipsen.

It is a longer-acting version of octreotide, making its administration easier and helping with patient compliance. DR. COBIN

A sustained-release formulation of the somatostatin analogue lanreotide has been approved by the Food and Drug Administration for the long-term treatment of acromegaly patients who have had an inadequate response to or cannot be treated with surgery or radiotherapy.

Lanreotide is administered via a deep subcutaneous injection every 4 weeks for 3 months, after which time the dosage is adjusted based on the patient's response, which is determined by a reduction in serum growth hormone or insulin growth factor-1 (IGF-1) levels, as well as changes in symptoms of acromegaly, according to the labeling.

In the United States, the prolonged-release formulation of lanreotide, which the label says is a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin, is being marketed as Somatuline Depot.

The label cites two long-term, randomized multicenter studies of different doses of Somatuline Depot in patients with acromegaly. In a 1-year study, 108 patients with active acromegaly were randomized to receive a 60-mg, 90-mg, or 120-mg injection of lanreotide or placebo, after which all patients received a fixed dose every 4 weeks for 4 months (4 injections), followed by a dose-titration phase of 8 injections for a total of 13 injections over 12 months. At the end of the first month, 63% of the patients treated with lanreotide had more than a 50% drop in mean growth hormone (GH) levels from baseline, compared with none of the 25 patients on placebo. At week 16, the end of the fixed dose phase, 72% of the lanreotide-treated patients had more than a 50% reduction in mean GH level, which was maintained for the rest of the study.

The second study described in the label was a 48-week, open-label, uncontrolled study of 63 patients with an IGF-1 level that was at least 1.3 times the upper limit of the age-adjusted normal range. During a 4-month fixed-dose phase, patients received four injections of 90 mg of Somatuline Depot every 4 weeks. This was followed by a dose-titration phase, during which the dose was adjusted based on GH and IGF-1 levels at the beginning of this phase, and again, if needed, after patients received another four injections. After 48 weeks, 43% of the patients achieved a normal age-adjusted IGF-1 concentration. The mean IGF-1 concentration after treatment was 1.3 ± 0.7 times the upper limit of normal, compared with 2.5 ± the upper limit of normal at baseline. The drop in IGF-1 levels “over time correlated with a corresponding marked decrease in GH concentrations,” according to the label, which cited the most common adverse reactions associated with treatment as diarrhea, cholelithiasis, abdominal pain, nausea, and injection site reactions.

Somatuline Depot, which has been available in Europe for a while, will be “a useful addition to our formularies,” Dr. Rhoda H. Cobin of Mount Sinai School of Medicine, New York, said in an interview. It is a longer-acting version of octreotide, used in the United States, which makes administration easier and will help with patient compliance, said Dr. Cobin, the immediate past president of the American College of Endocrinology and past president of the American Association of Clinical Endocrinologists.

Somatuline Depot is manufactured by Ipsen. Tercica, has the U.S. distribution rights and expects to launch the drug in the fourth quarter of 2007, according to Ipsen.

It is a longer-acting version of octreotide, making its administration easier and helping with patient compliance. DR. COBIN

A topical estradiol gel formulation has been approved for treating moderate to severe vasomotor symptoms associated with menopause. The gel is available under the trade name Elestrin from BioSante Pharmaceuticals Inc.

A transdermal product that is invisible is a good option “for women not wanting an oral product or where there's reason not to prescribe an oral product, and [for women who] are not keen on a visible patch,” said Dr. Wulf Utian, the executive director of the North American Menopause Society, and a consultant in women's health at the Cleveland Clinic. There are other estrogen gel products marketed; the 0.87-g dose of Elestrin is the lowest available dose of a gel product.

The Elestrin label contains contraindications, precautions, and warnings that are standard for the entire class of estrogen products.

In a 12-week study comparing different Elestrin doses with placebo in 484 symptomatic menopausal women with at least 60 moderate to severe hot flushes per week, the frequency and severity of hot flushes were significantly reduced by week 4 in the women on the 1.7-g daily dose and by week 5 in the women on 0.87-g daily dose, compared with those on placebo. The reductions in severity and frequency remained significant compared with placebo at 12 weeks of treatment, at which time the women on the higher dose had a mean of about three hot flushes per day, those on the lower dose had a mean of about five per day, and those on placebo had a mean of about eight per day.

Elestrin is applied in a thin layer to the upper arm once a day, starting at the lower approved dose, 0.87 g/day (0.52 mg of estradiol). If needed, dosage can be increased to 1.7 g/day (1.04 mg estradiol). (One pump actuation of the Elestrin applicator delivers 0.87 g; two actuations deliver 1.7 g.)

As in other dose-comparison studies of estrogen products, the Elestrin study showed that the lower dose takes a little more time to be effective but then is almost as effective as the higher dose, said Dr. Utian, an investigator in the study. “You get virtually the same level of efficacy, but it just takes a week or so longer to kick in, so the recommendation in practice is to advise the women that a low dose may take a little longer to reach efficacy, but don't start swapping doses too soon for higher doses because it's worth waiting.”

The general belief is that the lower the estrogen dose, the less likely it is that there will be side effects, such as thromboembolism; this is “probably true,” but there are still no long-term data confirming this, he said.

Dr. Utian said he has no financial ties to BioSante Pharmaceuticals.

A topical estradiol gel formulation has been approved for treating moderate to severe vasomotor symptoms associated with menopause. The gel is available under the trade name Elestrin from BioSante Pharmaceuticals Inc.

A transdermal product that is invisible is a good option “for women not wanting an oral product or where there's reason not to prescribe an oral product, and [for women who] are not keen on a visible patch,” said Dr. Wulf Utian, the executive director of the North American Menopause Society, and a consultant in women's health at the Cleveland Clinic. There are other estrogen gel products marketed; the 0.87-g dose of Elestrin is the lowest available dose of a gel product.

The Elestrin label contains contraindications, precautions, and warnings that are standard for the entire class of estrogen products.

In a 12-week study comparing different Elestrin doses with placebo in 484 symptomatic menopausal women with at least 60 moderate to severe hot flushes per week, the frequency and severity of hot flushes were significantly reduced by week 4 in the women on the 1.7-g daily dose and by week 5 in the women on 0.87-g daily dose, compared with those on placebo. The reductions in severity and frequency remained significant compared with placebo at 12 weeks of treatment, at which time the women on the higher dose had a mean of about three hot flushes per day, those on the lower dose had a mean of about five per day, and those on placebo had a mean of about eight per day.

Elestrin is applied in a thin layer to the upper arm once a day, starting at the lower approved dose, 0.87 g/day (0.52 mg of estradiol). If needed, dosage can be increased to 1.7 g/day (1.04 mg estradiol). (One pump actuation of the Elestrin applicator delivers 0.87 g; two actuations deliver 1.7 g.)

As in other dose-comparison studies of estrogen products, the Elestrin study showed that the lower dose takes a little more time to be effective but then is almost as effective as the higher dose, said Dr. Utian, an investigator in the study. “You get virtually the same level of efficacy, but it just takes a week or so longer to kick in, so the recommendation in practice is to advise the women that a low dose may take a little longer to reach efficacy, but don't start swapping doses too soon for higher doses because it's worth waiting.”

The general belief is that the lower the estrogen dose, the less likely it is that there will be side effects, such as thromboembolism; this is “probably true,” but there are still no long-term data confirming this, he said.

Dr. Utian said he has no financial ties to BioSante Pharmaceuticals.

A topical estradiol gel formulation has been approved for treating moderate to severe vasomotor symptoms associated with menopause. The gel is available under the trade name Elestrin from BioSante Pharmaceuticals Inc.

A transdermal product that is invisible is a good option “for women not wanting an oral product or where there's reason not to prescribe an oral product, and [for women who] are not keen on a visible patch,” said Dr. Wulf Utian, the executive director of the North American Menopause Society, and a consultant in women's health at the Cleveland Clinic. There are other estrogen gel products marketed; the 0.87-g dose of Elestrin is the lowest available dose of a gel product.

The Elestrin label contains contraindications, precautions, and warnings that are standard for the entire class of estrogen products.

In a 12-week study comparing different Elestrin doses with placebo in 484 symptomatic menopausal women with at least 60 moderate to severe hot flushes per week, the frequency and severity of hot flushes were significantly reduced by week 4 in the women on the 1.7-g daily dose and by week 5 in the women on 0.87-g daily dose, compared with those on placebo. The reductions in severity and frequency remained significant compared with placebo at 12 weeks of treatment, at which time the women on the higher dose had a mean of about three hot flushes per day, those on the lower dose had a mean of about five per day, and those on placebo had a mean of about eight per day.

Elestrin is applied in a thin layer to the upper arm once a day, starting at the lower approved dose, 0.87 g/day (0.52 mg of estradiol). If needed, dosage can be increased to 1.7 g/day (1.04 mg estradiol). (One pump actuation of the Elestrin applicator delivers 0.87 g; two actuations deliver 1.7 g.)

As in other dose-comparison studies of estrogen products, the Elestrin study showed that the lower dose takes a little more time to be effective but then is almost as effective as the higher dose, said Dr. Utian, an investigator in the study. “You get virtually the same level of efficacy, but it just takes a week or so longer to kick in, so the recommendation in practice is to advise the women that a low dose may take a little longer to reach efficacy, but don't start swapping doses too soon for higher doses because it's worth waiting.”

The general belief is that the lower the estrogen dose, the less likely it is that there will be side effects, such as thromboembolism; this is “probably true,” but there are still no long-term data confirming this, he said.

Dr. Utian said he has no financial ties to BioSante Pharmaceuticals.

The FDA's Web site on unapproved drugs is available at www.fda.gov/cder/drug/unapproved_drugs/default.htm

With one exception, timed-release drug products available in the United States that contain the expectorant guaifenesin have not been approved by the Food and Drug Administration and should be taken off the market, according to an agency announcement.

About 20 companies manufacture these products, most of which are available only by prescription. The products include Guaifenex (manufactured by Ethex Corp.), Crantex and Guaifen (Breckenridge Pharmaceutical Inc.), Amibid and Amitex (Actavis Group), Duraphen (Proethic Pharmaceuticals Inc.), Wellbid (Prasco), Ambi (Ambi Pharmaceuticals Inc.), and Maxifed (MCR American Pharmaceuticals Inc.). Many of the products include other active ingredients, the FDA announcement noted.

The FDA ordered manufacturers of these unapproved products to stop making them by Aug. 27 and to cease interstate shipment by Nov. 25, although some inventory will remain in pharmacies after that time.

The action does not affect immediate-release formulations of guaifenesin, only timed-release formulations, which are also described as extended release, long acting, or sustained release.

The only timed-release products containing guaifenesin that have been formally approved by the FDA are those marketed over the counter as Mucinex or Humibid, by Adams Respiratory Therapeutics. Besides Mucinex and Humibid, which contain only guaifenesin, the company makes Mucinex-D, which also contains pseudoephedrine, and Mucinex-DM, which also contains dextromethorphan.

Timed-release products need to be approved because the FDA needs to ensure that “the product releases its active ingredients safely and effectively, sustaining the intended effect over the entire time in which the product is intended to work,” according to the FDA statement.

Dose dumping is a major concern with these products, said Deborah M. Autor, an attorney and director of the office of compliance in the FDA's Center for Drug Evaluation and Research (CDER), during a telebriefing.

The FDA did not look into whether there were any reports of adverse events linked to the unapproved guaifenesin products; adverse event reports did not spur this action, Ms. Autor said.

The FDA's Web site on unapproved drugs is available at www.fda.gov/cder/drug/unapproved_drugs/default.htm

With one exception, timed-release drug products available in the United States that contain the expectorant guaifenesin have not been approved by the Food and Drug Administration and should be taken off the market, according to an agency announcement.

About 20 companies manufacture these products, most of which are available only by prescription. The products include Guaifenex (manufactured by Ethex Corp.), Crantex and Guaifen (Breckenridge Pharmaceutical Inc.), Amibid and Amitex (Actavis Group), Duraphen (Proethic Pharmaceuticals Inc.), Wellbid (Prasco), Ambi (Ambi Pharmaceuticals Inc.), and Maxifed (MCR American Pharmaceuticals Inc.). Many of the products include other active ingredients, the FDA announcement noted.

The FDA ordered manufacturers of these unapproved products to stop making them by Aug. 27 and to cease interstate shipment by Nov. 25, although some inventory will remain in pharmacies after that time.

The action does not affect immediate-release formulations of guaifenesin, only timed-release formulations, which are also described as extended release, long acting, or sustained release.

The only timed-release products containing guaifenesin that have been formally approved by the FDA are those marketed over the counter as Mucinex or Humibid, by Adams Respiratory Therapeutics. Besides Mucinex and Humibid, which contain only guaifenesin, the company makes Mucinex-D, which also contains pseudoephedrine, and Mucinex-DM, which also contains dextromethorphan.

Timed-release products need to be approved because the FDA needs to ensure that “the product releases its active ingredients safely and effectively, sustaining the intended effect over the entire time in which the product is intended to work,” according to the FDA statement.

Dose dumping is a major concern with these products, said Deborah M. Autor, an attorney and director of the office of compliance in the FDA's Center for Drug Evaluation and Research (CDER), during a telebriefing.

The FDA did not look into whether there were any reports of adverse events linked to the unapproved guaifenesin products; adverse event reports did not spur this action, Ms. Autor said.

The FDA's Web site on unapproved drugs is available at www.fda.gov/cder/drug/unapproved_drugs/default.htm

With one exception, timed-release drug products available in the United States that contain the expectorant guaifenesin have not been approved by the Food and Drug Administration and should be taken off the market, according to an agency announcement.

About 20 companies manufacture these products, most of which are available only by prescription. The products include Guaifenex (manufactured by Ethex Corp.), Crantex and Guaifen (Breckenridge Pharmaceutical Inc.), Amibid and Amitex (Actavis Group), Duraphen (Proethic Pharmaceuticals Inc.), Wellbid (Prasco), Ambi (Ambi Pharmaceuticals Inc.), and Maxifed (MCR American Pharmaceuticals Inc.). Many of the products include other active ingredients, the FDA announcement noted.

The FDA ordered manufacturers of these unapproved products to stop making them by Aug. 27 and to cease interstate shipment by Nov. 25, although some inventory will remain in pharmacies after that time.

The action does not affect immediate-release formulations of guaifenesin, only timed-release formulations, which are also described as extended release, long acting, or sustained release.

The only timed-release products containing guaifenesin that have been formally approved by the FDA are those marketed over the counter as Mucinex or Humibid, by Adams Respiratory Therapeutics. Besides Mucinex and Humibid, which contain only guaifenesin, the company makes Mucinex-D, which also contains pseudoephedrine, and Mucinex-DM, which also contains dextromethorphan.

Timed-release products need to be approved because the FDA needs to ensure that “the product releases its active ingredients safely and effectively, sustaining the intended effect over the entire time in which the product is intended to work,” according to the FDA statement.

Dose dumping is a major concern with these products, said Deborah M. Autor, an attorney and director of the office of compliance in the FDA's Center for Drug Evaluation and Research (CDER), during a telebriefing.

The FDA did not look into whether there were any reports of adverse events linked to the unapproved guaifenesin products; adverse event reports did not spur this action, Ms. Autor said.

A rating system that would use stars on the label of a sunscreen to indicate the degree of ultraviolet A protection provided by the product is among the main elements of a long-awaited Food and Drug Administration proposed regulation on sunscreen labeling.

Other main features of the proposed regulation include the requirement that a bolded warning be placed in the “Drug Facts” box that ultraviolet sun exposure “increases the risk of skin cancer, premature skin aging, and other skin damage,” and that it is important to reduce ultraviolet exposure “by limiting time in the sun, wearing protective clothing, and using a sunscreen.”

The proposed UVA rating would be based on a standard testing protocol using an in vivo and an in vitro test. The maximum sun protection factor (SPF) claim allowed would also be increased from SPF 30+ to SPF 50+.

The proposed rule amends the 1999 rule that addressed UVB testing and labeling requirements for sunscreen products, which was stayed to allow the agency to address testing and labeling requirements for the UVA protection provided by sunscreen products, according to the FDA.

The FDA proposal “identifies how to label sunscreens so that consumers can clearly understand the level of UVA and UVB protection sunscreens provide and to understand the importance of protecting themselves from both types of UV light,” Matthew R. Holman, Ph.D., a senior scientific reviewer in the FDA's Office of Nonprescription Products (ONP), said during a teleconference held on Aug. 23. The proposed label “would help consumers quickly and easily identify the level of UVA protection a sunscreen product offers,” with the term UVA clearly labeled on the package, followed by one to four stars, corresponding to low, medium, high or highest UVA protection. This rating will appear in equally prominent print to the UVB rating.

“Until now, much of the focus has been on reducing the exposure of UVB light while we worked to understand the science of assessing the effects of UVA light,” said Dr. Douglas Throckmorton, deputy director of the FDA's Center for Drug Evaluation and Research (CDER).

Determining how to accurately measure UVA protection has been challenging because there are no internationally accepted standards for evaluating the effectiveness of a sunscreen that protects against UVA, and there are about 12 different tests. The standardized testing protocol proposed by the FDA is based on the agency's analyses of data and information on available testing methods.

The changes would likely not appear until 2009 at the earliest, considering the 90-day comment period following the announcement, the time the FDA will take to consider comments and finalize the rule, and the time manufacturers would take to comply with the requirements.

The American Academy of Dermatology has been waiting for the FDA to propose rules about UVA in sunscreen since 1999.

“We think this will be an excellent way for consumers to evaluate sunscreen products,” said Dr. Diane Baker, president of the American Academy of Dermatology. The four-star system is “simple and easy to understand, and they are making an excellent effort to educate the public about the difference between UVA and UVB,” which has been confusing for consumers, she added.

Both Dr. Baker, who is in private practice in Portland, Ore., and Dr. Henry Lim, chair of dermatology at Henry Ford Hospital, Detroit, and chair of the Academy's council of science and research, commended the proposal to add the sun alert statement that emphasizes the risk of sun exposure, the importance of wearing protective clothing and limiting sun exposure, in addition to using sunscreen.

This is a “very reasonable proposal” to address UVA protection, in addition to UVB protection in sunscreens, Dr. Lim said in an interview. While the recommendations are long overdue, the issue of UVA protection is complex, so it took time for the FDA to come up with the final recommendations of the specific in vitro and in vivo methods.

This proposal is a “long time coming and … is a welcome step forward,” said Dr. Allan Halpern, chief of the dermatology service at Memorial Sloan Kettering Cancer Center in New York. Using both an in vivo and an in vitro test to assess UVA protection “will hopefully address concerns raised about each test,” added Dr. Halpern.

He expressed hope that responses during the comment period won't slow down the process of implementing the regulations. He added that capping the SPF at 50+ is an improvement, but was concerned that this might be a disincentive for the manufacturing of ultrahigh SPF sunscreens.

Under the proposed regulation, manufacturers of over-the-counter sunscreen products would be required to test their products for UVA protection using a specific test to measure the product's ability to reduce the amount of UVA light that passes through it and a test that measures the product's ability to prevent tanning. The UVA rating would be based on the lowest of the two test results. If a manufacturer does not perform the tests, or the tests find no UVA protection, then the label will have to state “no UVA protection.”

UVB protection will continue to be based on the SPF rating, but the FDA has proposed changes to the SPF testing methods to make the results more accurate and reproducible.

Under the regulation, companies would also be able to combine avobenzone with either zinc oxide or ensulizole, which Dr. Holman said would increase the number of sunscreen products available. The agency would consider revising the upper SPF limit allowed in the packages if data become available that support accurate testing of sunscreens with an SPF greater than 50.

During the comment period, the FDA is requesting comments and more information about the safety of sunscreen ingredients that use nanotechnology, because of the potential risk of nanoparticle ingredients penetrating consumers' skin, and on novel sunscreen formulations, such as foams, sprays, and towelettes. The proposal does not apply to insect repellant products combined with sunscreens, but it does apply to cosmetic products that contain sunscreen and SPF claims.

The FDA is accepting written comment on the proposal for 90 days following the announcement, until Nov. 26.

More information, including how to makea written comment, is available online at www.fda.gov/cder/drug/infopage/sunscreen/default.htm.

A rating system that would use stars on the label of a sunscreen to indicate the degree of ultraviolet A protection provided by the product is among the main elements of a long-awaited Food and Drug Administration proposed regulation on sunscreen labeling.

Other main features of the proposed regulation include the requirement that a bolded warning be placed in the “Drug Facts” box that ultraviolet sun exposure “increases the risk of skin cancer, premature skin aging, and other skin damage,” and that it is important to reduce ultraviolet exposure “by limiting time in the sun, wearing protective clothing, and using a sunscreen.”

The proposed UVA rating would be based on a standard testing protocol using an in vivo and an in vitro test. The maximum sun protection factor (SPF) claim allowed would also be increased from SPF 30+ to SPF 50+.

The proposed rule amends the 1999 rule that addressed UVB testing and labeling requirements for sunscreen products, which was stayed to allow the agency to address testing and labeling requirements for the UVA protection provided by sunscreen products, according to the FDA.

The FDA proposal “identifies how to label sunscreens so that consumers can clearly understand the level of UVA and UVB protection sunscreens provide and to understand the importance of protecting themselves from both types of UV light,” Matthew R. Holman, Ph.D., a senior scientific reviewer in the FDA's Office of Nonprescription Products (ONP), said during a teleconference held on Aug. 23. The proposed label “would help consumers quickly and easily identify the level of UVA protection a sunscreen product offers,” with the term UVA clearly labeled on the package, followed by one to four stars, corresponding to low, medium, high or highest UVA protection. This rating will appear in equally prominent print to the UVB rating.

“Until now, much of the focus has been on reducing the exposure of UVB light while we worked to understand the science of assessing the effects of UVA light,” said Dr. Douglas Throckmorton, deputy director of the FDA's Center for Drug Evaluation and Research (CDER).

Determining how to accurately measure UVA protection has been challenging because there are no internationally accepted standards for evaluating the effectiveness of a sunscreen that protects against UVA, and there are about 12 different tests. The standardized testing protocol proposed by the FDA is based on the agency's analyses of data and information on available testing methods.

The changes would likely not appear until 2009 at the earliest, considering the 90-day comment period following the announcement, the time the FDA will take to consider comments and finalize the rule, and the time manufacturers would take to comply with the requirements.

The American Academy of Dermatology has been waiting for the FDA to propose rules about UVA in sunscreen since 1999.

“We think this will be an excellent way for consumers to evaluate sunscreen products,” said Dr. Diane Baker, president of the American Academy of Dermatology. The four-star system is “simple and easy to understand, and they are making an excellent effort to educate the public about the difference between UVA and UVB,” which has been confusing for consumers, she added.

Both Dr. Baker, who is in private practice in Portland, Ore., and Dr. Henry Lim, chair of dermatology at Henry Ford Hospital, Detroit, and chair of the Academy's council of science and research, commended the proposal to add the sun alert statement that emphasizes the risk of sun exposure, the importance of wearing protective clothing and limiting sun exposure, in addition to using sunscreen.

This is a “very reasonable proposal” to address UVA protection, in addition to UVB protection in sunscreens, Dr. Lim said in an interview. While the recommendations are long overdue, the issue of UVA protection is complex, so it took time for the FDA to come up with the final recommendations of the specific in vitro and in vivo methods.

This proposal is a “long time coming and … is a welcome step forward,” said Dr. Allan Halpern, chief of the dermatology service at Memorial Sloan Kettering Cancer Center in New York. Using both an in vivo and an in vitro test to assess UVA protection “will hopefully address concerns raised about each test,” added Dr. Halpern.

He expressed hope that responses during the comment period won't slow down the process of implementing the regulations. He added that capping the SPF at 50+ is an improvement, but was concerned that this might be a disincentive for the manufacturing of ultrahigh SPF sunscreens.

Under the proposed regulation, manufacturers of over-the-counter sunscreen products would be required to test their products for UVA protection using a specific test to measure the product's ability to reduce the amount of UVA light that passes through it and a test that measures the product's ability to prevent tanning. The UVA rating would be based on the lowest of the two test results. If a manufacturer does not perform the tests, or the tests find no UVA protection, then the label will have to state “no UVA protection.”

UVB protection will continue to be based on the SPF rating, but the FDA has proposed changes to the SPF testing methods to make the results more accurate and reproducible.

Under the regulation, companies would also be able to combine avobenzone with either zinc oxide or ensulizole, which Dr. Holman said would increase the number of sunscreen products available. The agency would consider revising the upper SPF limit allowed in the packages if data become available that support accurate testing of sunscreens with an SPF greater than 50.

During the comment period, the FDA is requesting comments and more information about the safety of sunscreen ingredients that use nanotechnology, because of the potential risk of nanoparticle ingredients penetrating consumers' skin, and on novel sunscreen formulations, such as foams, sprays, and towelettes. The proposal does not apply to insect repellant products combined with sunscreens, but it does apply to cosmetic products that contain sunscreen and SPF claims.

The FDA is accepting written comment on the proposal for 90 days following the announcement, until Nov. 26.

More information, including how to makea written comment, is available online at www.fda.gov/cder/drug/infopage/sunscreen/default.htm.

A rating system that would use stars on the label of a sunscreen to indicate the degree of ultraviolet A protection provided by the product is among the main elements of a long-awaited Food and Drug Administration proposed regulation on sunscreen labeling.

Other main features of the proposed regulation include the requirement that a bolded warning be placed in the “Drug Facts” box that ultraviolet sun exposure “increases the risk of skin cancer, premature skin aging, and other skin damage,” and that it is important to reduce ultraviolet exposure “by limiting time in the sun, wearing protective clothing, and using a sunscreen.”

The proposed UVA rating would be based on a standard testing protocol using an in vivo and an in vitro test. The maximum sun protection factor (SPF) claim allowed would also be increased from SPF 30+ to SPF 50+.

The proposed rule amends the 1999 rule that addressed UVB testing and labeling requirements for sunscreen products, which was stayed to allow the agency to address testing and labeling requirements for the UVA protection provided by sunscreen products, according to the FDA.

The FDA proposal “identifies how to label sunscreens so that consumers can clearly understand the level of UVA and UVB protection sunscreens provide and to understand the importance of protecting themselves from both types of UV light,” Matthew R. Holman, Ph.D., a senior scientific reviewer in the FDA's Office of Nonprescription Products (ONP), said during a teleconference held on Aug. 23. The proposed label “would help consumers quickly and easily identify the level of UVA protection a sunscreen product offers,” with the term UVA clearly labeled on the package, followed by one to four stars, corresponding to low, medium, high or highest UVA protection. This rating will appear in equally prominent print to the UVB rating.

“Until now, much of the focus has been on reducing the exposure of UVB light while we worked to understand the science of assessing the effects of UVA light,” said Dr. Douglas Throckmorton, deputy director of the FDA's Center for Drug Evaluation and Research (CDER).

Determining how to accurately measure UVA protection has been challenging because there are no internationally accepted standards for evaluating the effectiveness of a sunscreen that protects against UVA, and there are about 12 different tests. The standardized testing protocol proposed by the FDA is based on the agency's analyses of data and information on available testing methods.

The changes would likely not appear until 2009 at the earliest, considering the 90-day comment period following the announcement, the time the FDA will take to consider comments and finalize the rule, and the time manufacturers would take to comply with the requirements.

The American Academy of Dermatology has been waiting for the FDA to propose rules about UVA in sunscreen since 1999.

“We think this will be an excellent way for consumers to evaluate sunscreen products,” said Dr. Diane Baker, president of the American Academy of Dermatology. The four-star system is “simple and easy to understand, and they are making an excellent effort to educate the public about the difference between UVA and UVB,” which has been confusing for consumers, she added.

Both Dr. Baker, who is in private practice in Portland, Ore., and Dr. Henry Lim, chair of dermatology at Henry Ford Hospital, Detroit, and chair of the Academy's council of science and research, commended the proposal to add the sun alert statement that emphasizes the risk of sun exposure, the importance of wearing protective clothing and limiting sun exposure, in addition to using sunscreen.

This is a “very reasonable proposal” to address UVA protection, in addition to UVB protection in sunscreens, Dr. Lim said in an interview. While the recommendations are long overdue, the issue of UVA protection is complex, so it took time for the FDA to come up with the final recommendations of the specific in vitro and in vivo methods.

This proposal is a “long time coming and … is a welcome step forward,” said Dr. Allan Halpern, chief of the dermatology service at Memorial Sloan Kettering Cancer Center in New York. Using both an in vivo and an in vitro test to assess UVA protection “will hopefully address concerns raised about each test,” added Dr. Halpern.

He expressed hope that responses during the comment period won't slow down the process of implementing the regulations. He added that capping the SPF at 50+ is an improvement, but was concerned that this might be a disincentive for the manufacturing of ultrahigh SPF sunscreens.

Under the proposed regulation, manufacturers of over-the-counter sunscreen products would be required to test their products for UVA protection using a specific test to measure the product's ability to reduce the amount of UVA light that passes through it and a test that measures the product's ability to prevent tanning. The UVA rating would be based on the lowest of the two test results. If a manufacturer does not perform the tests, or the tests find no UVA protection, then the label will have to state “no UVA protection.”

UVB protection will continue to be based on the SPF rating, but the FDA has proposed changes to the SPF testing methods to make the results more accurate and reproducible.

Under the regulation, companies would also be able to combine avobenzone with either zinc oxide or ensulizole, which Dr. Holman said would increase the number of sunscreen products available. The agency would consider revising the upper SPF limit allowed in the packages if data become available that support accurate testing of sunscreens with an SPF greater than 50.

During the comment period, the FDA is requesting comments and more information about the safety of sunscreen ingredients that use nanotechnology, because of the potential risk of nanoparticle ingredients penetrating consumers' skin, and on novel sunscreen formulations, such as foams, sprays, and towelettes. The proposal does not apply to insect repellant products combined with sunscreens, but it does apply to cosmetic products that contain sunscreen and SPF claims.

The FDA is accepting written comment on the proposal for 90 days following the announcement, until Nov. 26.

More information, including how to makea written comment, is available online at www.fda.gov/cder/drug/infopage/sunscreen/default.htm.

The antiviral drug entecavir is not recommended for use in patients coinfected with HIV and hepatitis B who are not receiving highly active antiretroviral therapy, because this may promote HIV resistance, according to revised labeling for entecavir.

The black box warning for entecavir now includes the statement that “limited clinical experience suggests there is a potential for the development of resistance” to HIV nucleoside reverse transcriptase inhibitors “if Baraclude is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated.”

Baraclude is the trade name for entecavir, marketed by Bristol-Myers Squibb for treating chronic hepatitis B infection in adults.

Other changes in the labeling include the recommendation to offer HIV antibody testing to all patients before starting treatment with entecavir. The changes are summarized in a “Dear Healthcare Professional” letter issued in August by Bristol-Myers Squibb.

The letter and MedWatch summary are available at www.fda.gov/medwatch/safety/2007/safety07.htm#Baraclude

The antiviral drug entecavir is not recommended for use in patients coinfected with HIV and hepatitis B who are not receiving highly active antiretroviral therapy, because this may promote HIV resistance, according to revised labeling for entecavir.

The black box warning for entecavir now includes the statement that “limited clinical experience suggests there is a potential for the development of resistance” to HIV nucleoside reverse transcriptase inhibitors “if Baraclude is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated.”

Baraclude is the trade name for entecavir, marketed by Bristol-Myers Squibb for treating chronic hepatitis B infection in adults.

Other changes in the labeling include the recommendation to offer HIV antibody testing to all patients before starting treatment with entecavir. The changes are summarized in a “Dear Healthcare Professional” letter issued in August by Bristol-Myers Squibb.

The letter and MedWatch summary are available at www.fda.gov/medwatch/safety/2007/safety07.htm#Baraclude

The antiviral drug entecavir is not recommended for use in patients coinfected with HIV and hepatitis B who are not receiving highly active antiretroviral therapy, because this may promote HIV resistance, according to revised labeling for entecavir.

The black box warning for entecavir now includes the statement that “limited clinical experience suggests there is a potential for the development of resistance” to HIV nucleoside reverse transcriptase inhibitors “if Baraclude is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated.”

Baraclude is the trade name for entecavir, marketed by Bristol-Myers Squibb for treating chronic hepatitis B infection in adults.

Other changes in the labeling include the recommendation to offer HIV antibody testing to all patients before starting treatment with entecavir. The changes are summarized in a “Dear Healthcare Professional” letter issued in August by Bristol-Myers Squibb.

The letter and MedWatch summary are available at www.fda.gov/medwatch/safety/2007/safety07.htm#Baraclude

Brian Marson, assistant news editor for Elsevier's “The Pink Sheet,” contributed to this report.

The labels of all thiazolidinediones now carry a black box warning about the risk of heart failure, the Food and Drug Administration announced on Aug. 14.

The strengthened warning emphasizes that thiazolidinediones (TZDs) may “cause or exacerbate congestive heart failure in some patients,” according to the FDA.

The agency sent the manufacturers letters requesting the labeling change in May. Product labeling for the TZDs rosiglitazone (Avandia), manufactured by GlaxoSmithKline, and pioglitazone (Actos), manufactured by Takeda, previously contained information about heart failure (HF) in the warnings and precautions sections, but the labeling is being strengthened following recent revelations about rosiglitazone's cardiovascular safety.

The FDA says that the concern over heart failure is “separate” from the concerns over the increased MI risk associated with rosiglitazone, which was the subject of a joint meeting of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee in July.

The committees concluded then that data from meta-analyses of the rosiglitazone clinical program show an increased risk for myocardial ischemia for the type 2 diabetes therapy. The agency is currently reviewing similar pooled data from the pioglitazone clinical program.

“This new boxed warning addresses FDA's concerns that despite the warnings and information already listed in the drug labels, these drugs are still being prescribed to patients without careful monitoring for signs of heart failure,” Dr. Steven Galson, director of the FDA's Center for Drug Evaluation and Research, said in a statement.

“The strengthened warning advises health care professionals to observe patients carefully for the signs and symptoms of heart failure, including excessive, rapid weight gain, shortness of breath, and edema after starting drug therapy,” according to the FDA.

The updated labeling states that initiation of rosiglitazone or pioglitazone is contraindicated in patients with New York Heart Association class III or IV heart failure. After treatment with these products is initiated or if the dose is increased, patients should be observed for signs of heart failure. If a patient is diagnosed with heart failure, discontinuation or dose reduction of the TZD “should be considered.”

The rosiglitazone data cited by the FDA include a year-long echocardiographic study in type 2 diabetic patients with NYHA class I or II heart failure, who were receiving treatment for diabetes and HF; the study did not find treatment-related differences in the change from baseline in ejection fraction. But the risk of heart failure exacerbations was higher in patients on rosiglitazone (6%), compared with those on placebo (4%). In addition, the rates of worsening edema, worsening dyspnea, and increases in heart failure medications were higher among those on rosiglitazone (25%, 26%, and 33%, respectively), compared with those on placebo (9%, 17%, and 18%).

Among the pioglitazone data cited by the FDA was a 24-week study comparing the TZD to glyburide in 518 patients with NYHA class II and III heart failure and an ejection fraction below 40%. In the study, overnight hospitalizations for heart failure were reported in nearly 10% of those on pioglitazone, compared with almost 5% of those on glyburide, an adverse event that was “more marked” in patients taking insulin at baseline and in those older than age 64.

The label revision also extends to the combination products that include the TZDs: Avandaryl (rosiglitazone and glimepiride), Avandamet (rosiglitazone and metformin), and Duetact (pioglitazone and glimepiride).

The FDA is continuing to monitor postmarketing reports of heart failure; its review of rosiglitazone and the possible increased risk of MI also is ongoing.

For more information, go to: www.fda.gov/medwatch/safety/2007/safety07.htm#rosi_piowww.fda.gov/medwatch

Brian Marson, assistant news editor for Elsevier's “The Pink Sheet,” contributed to this report.

The labels of all thiazolidinediones now carry a black box warning about the risk of heart failure, the Food and Drug Administration announced on Aug. 14.

The strengthened warning emphasizes that thiazolidinediones (TZDs) may “cause or exacerbate congestive heart failure in some patients,” according to the FDA.

The agency sent the manufacturers letters requesting the labeling change in May. Product labeling for the TZDs rosiglitazone (Avandia), manufactured by GlaxoSmithKline, and pioglitazone (Actos), manufactured by Takeda, previously contained information about heart failure (HF) in the warnings and precautions sections, but the labeling is being strengthened following recent revelations about rosiglitazone's cardiovascular safety.

The FDA says that the concern over heart failure is “separate” from the concerns over the increased MI risk associated with rosiglitazone, which was the subject of a joint meeting of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee in July.

The committees concluded then that data from meta-analyses of the rosiglitazone clinical program show an increased risk for myocardial ischemia for the type 2 diabetes therapy. The agency is currently reviewing similar pooled data from the pioglitazone clinical program.

“This new boxed warning addresses FDA's concerns that despite the warnings and information already listed in the drug labels, these drugs are still being prescribed to patients without careful monitoring for signs of heart failure,” Dr. Steven Galson, director of the FDA's Center for Drug Evaluation and Research, said in a statement.

“The strengthened warning advises health care professionals to observe patients carefully for the signs and symptoms of heart failure, including excessive, rapid weight gain, shortness of breath, and edema after starting drug therapy,” according to the FDA.

The updated labeling states that initiation of rosiglitazone or pioglitazone is contraindicated in patients with New York Heart Association class III or IV heart failure. After treatment with these products is initiated or if the dose is increased, patients should be observed for signs of heart failure. If a patient is diagnosed with heart failure, discontinuation or dose reduction of the TZD “should be considered.”

The rosiglitazone data cited by the FDA include a year-long echocardiographic study in type 2 diabetic patients with NYHA class I or II heart failure, who were receiving treatment for diabetes and HF; the study did not find treatment-related differences in the change from baseline in ejection fraction. But the risk of heart failure exacerbations was higher in patients on rosiglitazone (6%), compared with those on placebo (4%). In addition, the rates of worsening edema, worsening dyspnea, and increases in heart failure medications were higher among those on rosiglitazone (25%, 26%, and 33%, respectively), compared with those on placebo (9%, 17%, and 18%).

Among the pioglitazone data cited by the FDA was a 24-week study comparing the TZD to glyburide in 518 patients with NYHA class II and III heart failure and an ejection fraction below 40%. In the study, overnight hospitalizations for heart failure were reported in nearly 10% of those on pioglitazone, compared with almost 5% of those on glyburide, an adverse event that was “more marked” in patients taking insulin at baseline and in those older than age 64.

The label revision also extends to the combination products that include the TZDs: Avandaryl (rosiglitazone and glimepiride), Avandamet (rosiglitazone and metformin), and Duetact (pioglitazone and glimepiride).

The FDA is continuing to monitor postmarketing reports of heart failure; its review of rosiglitazone and the possible increased risk of MI also is ongoing.

For more information, go to: www.fda.gov/medwatch/safety/2007/safety07.htm#rosi_piowww.fda.gov/medwatch

Brian Marson, assistant news editor for Elsevier's “The Pink Sheet,” contributed to this report.

The labels of all thiazolidinediones now carry a black box warning about the risk of heart failure, the Food and Drug Administration announced on Aug. 14.

The strengthened warning emphasizes that thiazolidinediones (TZDs) may “cause or exacerbate congestive heart failure in some patients,” according to the FDA.

The agency sent the manufacturers letters requesting the labeling change in May. Product labeling for the TZDs rosiglitazone (Avandia), manufactured by GlaxoSmithKline, and pioglitazone (Actos), manufactured by Takeda, previously contained information about heart failure (HF) in the warnings and precautions sections, but the labeling is being strengthened following recent revelations about rosiglitazone's cardiovascular safety.

The FDA says that the concern over heart failure is “separate” from the concerns over the increased MI risk associated with rosiglitazone, which was the subject of a joint meeting of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee in July.

The committees concluded then that data from meta-analyses of the rosiglitazone clinical program show an increased risk for myocardial ischemia for the type 2 diabetes therapy. The agency is currently reviewing similar pooled data from the pioglitazone clinical program.

“This new boxed warning addresses FDA's concerns that despite the warnings and information already listed in the drug labels, these drugs are still being prescribed to patients without careful monitoring for signs of heart failure,” Dr. Steven Galson, director of the FDA's Center for Drug Evaluation and Research, said in a statement.

“The strengthened warning advises health care professionals to observe patients carefully for the signs and symptoms of heart failure, including excessive, rapid weight gain, shortness of breath, and edema after starting drug therapy,” according to the FDA.

The updated labeling states that initiation of rosiglitazone or pioglitazone is contraindicated in patients with New York Heart Association class III or IV heart failure. After treatment with these products is initiated or if the dose is increased, patients should be observed for signs of heart failure. If a patient is diagnosed with heart failure, discontinuation or dose reduction of the TZD “should be considered.”

The rosiglitazone data cited by the FDA include a year-long echocardiographic study in type 2 diabetic patients with NYHA class I or II heart failure, who were receiving treatment for diabetes and HF; the study did not find treatment-related differences in the change from baseline in ejection fraction. But the risk of heart failure exacerbations was higher in patients on rosiglitazone (6%), compared with those on placebo (4%). In addition, the rates of worsening edema, worsening dyspnea, and increases in heart failure medications were higher among those on rosiglitazone (25%, 26%, and 33%, respectively), compared with those on placebo (9%, 17%, and 18%).

Among the pioglitazone data cited by the FDA was a 24-week study comparing the TZD to glyburide in 518 patients with NYHA class II and III heart failure and an ejection fraction below 40%. In the study, overnight hospitalizations for heart failure were reported in nearly 10% of those on pioglitazone, compared with almost 5% of those on glyburide, an adverse event that was “more marked” in patients taking insulin at baseline and in those older than age 64.

The label revision also extends to the combination products that include the TZDs: Avandaryl (rosiglitazone and glimepiride), Avandamet (rosiglitazone and metformin), and Duetact (pioglitazone and glimepiride).

The FDA is continuing to monitor postmarketing reports of heart failure; its review of rosiglitazone and the possible increased risk of MI also is ongoing.

For more information, go to: www.fda.gov/medwatch/safety/2007/safety07.htm#rosi_piowww.fda.gov/medwatch

The intravenous bisphosphonate zoledronic acid (Reclast) has been approved as the first treatment for postmenopausal osteoporosis that is administered once a year.

The approved dosage of zoledronic acid is a single 5-mg infusion given intravenously, over no less than 15 minutes, annually. The approval was announced in August by the drug's manufacturer, Novartis Pharmaceuticals Corporation.

The 5-mg formulation of intravenous zoledronic acid was first approved earlier this year as a treatment for Paget disease. Zoledronic acid has been available in a 4-mg formulation (Zometa) for oncology indications, which is still available and should not be used in a patient taking Reclast.

Like other bisphosphonates, zoledronic acid inhibits osteoclast-mediated bone resorption. Daily, weekly, or monthly dosing schedules for oral bisphosphonate drugs previously have been approved by the Food and Drug Administration. An injectable form of the bisphosphonate ibandronate (Boniva) is approved for use every 3 months for postmenopausal osteoporosis.

The average wholesale acquisition price for each zoledronic acid 5-mg dose is $1,041.00, but the retail price may vary, a Novartis spokesperson said.

Approval for the osteoporosis indication was based on a 3-year, international study of more than 7,700 women with postmenopausal osteoporosis, the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial.

The study, which was published in May, found that women who received an annual 5-mg intravenous infusion of zoledronic acid had a 70% lower risk of vertebral fractures over a 3-year period, compared with women who were taking placebo.

Vertebral fracture occurred in 3.3% of the zoledronic acid group and 10.9% of the placebo group (N. Engl. J. Med. 2007;356:1809-22).

Hip fracture occurred in 1.4% of the zoledronic acid group and 2.5% of the placebo group, which represented a 41% reduction in the risk of hip fracture with active treatment.

Compared with placebo, zoledronic acid treatment also was associated with a significant reduction in nonvertebral fractures, clinical fractures, and clinical vertebral fractures, and significant improvements in bone mineral density and bone metabolism markers. These differences between groups were all statistically significant.

“Given the relatively poor adherence to oral bisphosphonate therapy in clinical practice, annual infusion of zoledronic acid may provide a promising approach to reducing fracture risk,” the study authors concluded.

The study was supported by Novartis, and two authors were from Novartis.

“This is the first study where we have evidence for [a reduction in] spine, hip, and non-vertebral fractures all in the same trial,” Dr. Nelson B. Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, said in an interview. Dr. Watts, one of the investigators in the trial, said that based on these efficacy data, he ranks this drug with the bisphosphonates alendronate (Fosamax) and risedronate (Actonel), which also have been shown to reduce the risks of these three significant fracture types.

Dr. Watts disclosed that he is a consultant to Novartis.

He attributes part of the drug's effectiveness to compliance. “Once the patients receive the dose, they have at least a year's worth of drug on board,” he said, noting that one of the problems with treating silent diseases like osteoporosis is that a substantial proportion of patients stop taking the drug within 6-7 months of starting treatment for the disease.

Dr. Watts said that about one-third of patients have an acute phase response, with a fever, muscle aches, and other flu-like symptoms, but if they are premedicated with acetaminophen or ibuprofen, they are less likely to have those symptoms, or the symptoms, if they occur, are less severe.

This is also a first-dose phenomenon, so whether patients do or do not have these symptoms with the first dose, they are unlikely to experience the symptoms with subsequent doses, he added.

The intravenous bisphosphonate zoledronic acid (Reclast) has been approved as the first treatment for postmenopausal osteoporosis that is administered once a year.

The approved dosage of zoledronic acid is a single 5-mg infusion given intravenously, over no less than 15 minutes, annually. The approval was announced in August by the drug's manufacturer, Novartis Pharmaceuticals Corporation.

The 5-mg formulation of intravenous zoledronic acid was first approved earlier this year as a treatment for Paget disease. Zoledronic acid has been available in a 4-mg formulation (Zometa) for oncology indications, which is still available and should not be used in a patient taking Reclast.

Like other bisphosphonates, zoledronic acid inhibits osteoclast-mediated bone resorption. Daily, weekly, or monthly dosing schedules for oral bisphosphonate drugs previously have been approved by the Food and Drug Administration. An injectable form of the bisphosphonate ibandronate (Boniva) is approved for use every 3 months for postmenopausal osteoporosis.

The average wholesale acquisition price for each zoledronic acid 5-mg dose is $1,041.00, but the retail price may vary, a Novartis spokesperson said.

Approval for the osteoporosis indication was based on a 3-year, international study of more than 7,700 women with postmenopausal osteoporosis, the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial.

The study, which was published in May, found that women who received an annual 5-mg intravenous infusion of zoledronic acid had a 70% lower risk of vertebral fractures over a 3-year period, compared with women who were taking placebo.

Vertebral fracture occurred in 3.3% of the zoledronic acid group and 10.9% of the placebo group (N. Engl. J. Med. 2007;356:1809-22).

Hip fracture occurred in 1.4% of the zoledronic acid group and 2.5% of the placebo group, which represented a 41% reduction in the risk of hip fracture with active treatment.

Compared with placebo, zoledronic acid treatment also was associated with a significant reduction in nonvertebral fractures, clinical fractures, and clinical vertebral fractures, and significant improvements in bone mineral density and bone metabolism markers. These differences between groups were all statistically significant.

“Given the relatively poor adherence to oral bisphosphonate therapy in clinical practice, annual infusion of zoledronic acid may provide a promising approach to reducing fracture risk,” the study authors concluded.

The study was supported by Novartis, and two authors were from Novartis.

“This is the first study where we have evidence for [a reduction in] spine, hip, and non-vertebral fractures all in the same trial,” Dr. Nelson B. Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, said in an interview. Dr. Watts, one of the investigators in the trial, said that based on these efficacy data, he ranks this drug with the bisphosphonates alendronate (Fosamax) and risedronate (Actonel), which also have been shown to reduce the risks of these three significant fracture types.

Dr. Watts disclosed that he is a consultant to Novartis.

He attributes part of the drug's effectiveness to compliance. “Once the patients receive the dose, they have at least a year's worth of drug on board,” he said, noting that one of the problems with treating silent diseases like osteoporosis is that a substantial proportion of patients stop taking the drug within 6-7 months of starting treatment for the disease.

Dr. Watts said that about one-third of patients have an acute phase response, with a fever, muscle aches, and other flu-like symptoms, but if they are premedicated with acetaminophen or ibuprofen, they are less likely to have those symptoms, or the symptoms, if they occur, are less severe.

This is also a first-dose phenomenon, so whether patients do or do not have these symptoms with the first dose, they are unlikely to experience the symptoms with subsequent doses, he added.

The intravenous bisphosphonate zoledronic acid (Reclast) has been approved as the first treatment for postmenopausal osteoporosis that is administered once a year.

The approved dosage of zoledronic acid is a single 5-mg infusion given intravenously, over no less than 15 minutes, annually. The approval was announced in August by the drug's manufacturer, Novartis Pharmaceuticals Corporation.

The 5-mg formulation of intravenous zoledronic acid was first approved earlier this year as a treatment for Paget disease. Zoledronic acid has been available in a 4-mg formulation (Zometa) for oncology indications, which is still available and should not be used in a patient taking Reclast.

Like other bisphosphonates, zoledronic acid inhibits osteoclast-mediated bone resorption. Daily, weekly, or monthly dosing schedules for oral bisphosphonate drugs previously have been approved by the Food and Drug Administration. An injectable form of the bisphosphonate ibandronate (Boniva) is approved for use every 3 months for postmenopausal osteoporosis.

The average wholesale acquisition price for each zoledronic acid 5-mg dose is $1,041.00, but the retail price may vary, a Novartis spokesperson said.

Approval for the osteoporosis indication was based on a 3-year, international study of more than 7,700 women with postmenopausal osteoporosis, the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial.

The study, which was published in May, found that women who received an annual 5-mg intravenous infusion of zoledronic acid had a 70% lower risk of vertebral fractures over a 3-year period, compared with women who were taking placebo.

Vertebral fracture occurred in 3.3% of the zoledronic acid group and 10.9% of the placebo group (N. Engl. J. Med. 2007;356:1809-22).

Hip fracture occurred in 1.4% of the zoledronic acid group and 2.5% of the placebo group, which represented a 41% reduction in the risk of hip fracture with active treatment.

Compared with placebo, zoledronic acid treatment also was associated with a significant reduction in nonvertebral fractures, clinical fractures, and clinical vertebral fractures, and significant improvements in bone mineral density and bone metabolism markers. These differences between groups were all statistically significant.

“Given the relatively poor adherence to oral bisphosphonate therapy in clinical practice, annual infusion of zoledronic acid may provide a promising approach to reducing fracture risk,” the study authors concluded.

The study was supported by Novartis, and two authors were from Novartis.

“This is the first study where we have evidence for [a reduction in] spine, hip, and non-vertebral fractures all in the same trial,” Dr. Nelson B. Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, said in an interview. Dr. Watts, one of the investigators in the trial, said that based on these efficacy data, he ranks this drug with the bisphosphonates alendronate (Fosamax) and risedronate (Actonel), which also have been shown to reduce the risks of these three significant fracture types.

Dr. Watts disclosed that he is a consultant to Novartis.

He attributes part of the drug's effectiveness to compliance. “Once the patients receive the dose, they have at least a year's worth of drug on board,” he said, noting that one of the problems with treating silent diseases like osteoporosis is that a substantial proportion of patients stop taking the drug within 6-7 months of starting treatment for the disease.

Dr. Watts said that about one-third of patients have an acute phase response, with a fever, muscle aches, and other flu-like symptoms, but if they are premedicated with acetaminophen or ibuprofen, they are less likely to have those symptoms, or the symptoms, if they occur, are less severe.

This is also a first-dose phenomenon, so whether patients do or do not have these symptoms with the first dose, they are unlikely to experience the symptoms with subsequent doses, he added.

A study of more than 18,000 infant records in a Medicaid database found that use of combination vaccines significantly improved immunization coverage rates of the vaccines studied in children through age 24 months.

This study “is the first in the United States to suggest a positive effect of combination vaccines on pediatric immunization coverage rates,” the authors concluded (Pediatr. Infect. Dis. J. 2007;26:496-500).

They pointed out that although there are clear advantages of combination vaccines, such as a reduction in pain and anxiety, there is not much evidence for other possible advantages of these vaccines.

Dr. Gary S. Marshall of the University of Louisville (Ky.) and his associates reviewed claims from the Georgia Medicaid Department of Community Health Medicaid Program on infants born from January 1 through September 30, 2003, evaluating vaccine coverage rates among 18,821 infants enrolled in the program through 24 months of age.

The 16,007 children in the combination cohort had received at least one dose of the combination vaccines containing the hepatitis B vaccine (HepB) and Haemophilus influenzae type b conjugate vaccine (Hib), marketed as Comvax, or Pediarix, which combines the diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP), HepB, and inactivated polio vaccine (IPV). The remaining 2,814 children had not received any doses of either combination vaccine. In the combination cohort, 68% had received at least one dose of HepB/Hib, and 44% had received at least one dose of DTaP/HepB/IPV.

The main outcome of the study was coverage rates (the percentage of children who received at least the recommended number of doses for each vaccine by 24 months of age). The vaccine series analyzed were the 4:3:1 series (four DTaP, three IPV, one MMR); 4:3:1:3:1 (four DTaP, three IPV, one MMR, three Hib, one varicella); and 3:3:3 (three DTaP, three IPV, three Hib).

After controlling for gender, birth quarter, race, rural or urban county of residence, and other potential confounders, the researchers found that having received at least one dose of a combination vaccine was independently associated with greater coverage rates for each vaccine or vaccine series at 24 months of age—except for MMR, Hib, and varicella.

For example, those who received a combination vaccine were 26% more likely to receive 4 DTaP vaccines, and 2.5 times more likely to receive 3 DTaP vaccines, and were 28% more likely to receive the 4:3:1 series, compared with those who had not received a combination vaccine.

The study had limitations, such as the potential for over- and underreporting of vaccinations in administrative claims databases, Dr. Marshall and associates noted. But they added that their results suggest that the use of combination vaccines has “the potential to remedy” problems in delivering all recommended vaccines at the recommended ages as new vaccines are introduced. Future studies could focus on other patient populations, such as those in the private sector, as well as the timeliness, cost, and other outcomes of combination vaccines, they suggested.

Dr. Marshall and some of the other researchers are from the University of Louisville, Ky; other investigators were from the Georgia Medicaid program and Xcenda. In the acknowledgments section of the study, Xcenda is listed as a research service company that was contracted by Pediarix manufacturer GlaxoSmithKline (GSK) to help conduct the study. It also stated that Dr. Marshall has been an investigator in clinical trials funded by GSK and competitors—including Sanofi Pasteur and Comvax manufacturer Merck—and has received honoraria for lectures and service on advisory board for these companies. Another author has been an investigator on clinical trials funded by Sanofi Pasteur and Merck, and has received honoraria for lectures and service on advisory boards for the companies.

A study of more than 18,000 infant records in a Medicaid database found that use of combination vaccines significantly improved immunization coverage rates of the vaccines studied in children through age 24 months.

This study “is the first in the United States to suggest a positive effect of combination vaccines on pediatric immunization coverage rates,” the authors concluded (Pediatr. Infect. Dis. J. 2007;26:496-500).

They pointed out that although there are clear advantages of combination vaccines, such as a reduction in pain and anxiety, there is not much evidence for other possible advantages of these vaccines.

Dr. Gary S. Marshall of the University of Louisville (Ky.) and his associates reviewed claims from the Georgia Medicaid Department of Community Health Medicaid Program on infants born from January 1 through September 30, 2003, evaluating vaccine coverage rates among 18,821 infants enrolled in the program through 24 months of age.

The 16,007 children in the combination cohort had received at least one dose of the combination vaccines containing the hepatitis B vaccine (HepB) and Haemophilus influenzae type b conjugate vaccine (Hib), marketed as Comvax, or Pediarix, which combines the diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP), HepB, and inactivated polio vaccine (IPV). The remaining 2,814 children had not received any doses of either combination vaccine. In the combination cohort, 68% had received at least one dose of HepB/Hib, and 44% had received at least one dose of DTaP/HepB/IPV.

The main outcome of the study was coverage rates (the percentage of children who received at least the recommended number of doses for each vaccine by 24 months of age). The vaccine series analyzed were the 4:3:1 series (four DTaP, three IPV, one MMR); 4:3:1:3:1 (four DTaP, three IPV, one MMR, three Hib, one varicella); and 3:3:3 (three DTaP, three IPV, three Hib).

After controlling for gender, birth quarter, race, rural or urban county of residence, and other potential confounders, the researchers found that having received at least one dose of a combination vaccine was independently associated with greater coverage rates for each vaccine or vaccine series at 24 months of age—except for MMR, Hib, and varicella.

For example, those who received a combination vaccine were 26% more likely to receive 4 DTaP vaccines, and 2.5 times more likely to receive 3 DTaP vaccines, and were 28% more likely to receive the 4:3:1 series, compared with those who had not received a combination vaccine.

The study had limitations, such as the potential for over- and underreporting of vaccinations in administrative claims databases, Dr. Marshall and associates noted. But they added that their results suggest that the use of combination vaccines has “the potential to remedy” problems in delivering all recommended vaccines at the recommended ages as new vaccines are introduced. Future studies could focus on other patient populations, such as those in the private sector, as well as the timeliness, cost, and other outcomes of combination vaccines, they suggested.

Dr. Marshall and some of the other researchers are from the University of Louisville, Ky; other investigators were from the Georgia Medicaid program and Xcenda. In the acknowledgments section of the study, Xcenda is listed as a research service company that was contracted by Pediarix manufacturer GlaxoSmithKline (GSK) to help conduct the study. It also stated that Dr. Marshall has been an investigator in clinical trials funded by GSK and competitors—including Sanofi Pasteur and Comvax manufacturer Merck—and has received honoraria for lectures and service on advisory board for these companies. Another author has been an investigator on clinical trials funded by Sanofi Pasteur and Merck, and has received honoraria for lectures and service on advisory boards for the companies.

A study of more than 18,000 infant records in a Medicaid database found that use of combination vaccines significantly improved immunization coverage rates of the vaccines studied in children through age 24 months.

This study “is the first in the United States to suggest a positive effect of combination vaccines on pediatric immunization coverage rates,” the authors concluded (Pediatr. Infect. Dis. J. 2007;26:496-500).

They pointed out that although there are clear advantages of combination vaccines, such as a reduction in pain and anxiety, there is not much evidence for other possible advantages of these vaccines.

Dr. Gary S. Marshall of the University of Louisville (Ky.) and his associates reviewed claims from the Georgia Medicaid Department of Community Health Medicaid Program on infants born from January 1 through September 30, 2003, evaluating vaccine coverage rates among 18,821 infants enrolled in the program through 24 months of age.

The 16,007 children in the combination cohort had received at least one dose of the combination vaccines containing the hepatitis B vaccine (HepB) and Haemophilus influenzae type b conjugate vaccine (Hib), marketed as Comvax, or Pediarix, which combines the diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP), HepB, and inactivated polio vaccine (IPV). The remaining 2,814 children had not received any doses of either combination vaccine. In the combination cohort, 68% had received at least one dose of HepB/Hib, and 44% had received at least one dose of DTaP/HepB/IPV.

The main outcome of the study was coverage rates (the percentage of children who received at least the recommended number of doses for each vaccine by 24 months of age). The vaccine series analyzed were the 4:3:1 series (four DTaP, three IPV, one MMR); 4:3:1:3:1 (four DTaP, three IPV, one MMR, three Hib, one varicella); and 3:3:3 (three DTaP, three IPV, three Hib).

After controlling for gender, birth quarter, race, rural or urban county of residence, and other potential confounders, the researchers found that having received at least one dose of a combination vaccine was independently associated with greater coverage rates for each vaccine or vaccine series at 24 months of age—except for MMR, Hib, and varicella.

For example, those who received a combination vaccine were 26% more likely to receive 4 DTaP vaccines, and 2.5 times more likely to receive 3 DTaP vaccines, and were 28% more likely to receive the 4:3:1 series, compared with those who had not received a combination vaccine.

The study had limitations, such as the potential for over- and underreporting of vaccinations in administrative claims databases, Dr. Marshall and associates noted. But they added that their results suggest that the use of combination vaccines has “the potential to remedy” problems in delivering all recommended vaccines at the recommended ages as new vaccines are introduced. Future studies could focus on other patient populations, such as those in the private sector, as well as the timeliness, cost, and other outcomes of combination vaccines, they suggested.

Dr. Marshall and some of the other researchers are from the University of Louisville, Ky; other investigators were from the Georgia Medicaid program and Xcenda. In the acknowledgments section of the study, Xcenda is listed as a research service company that was contracted by Pediarix manufacturer GlaxoSmithKline (GSK) to help conduct the study. It also stated that Dr. Marshall has been an investigator in clinical trials funded by GSK and competitors—including Sanofi Pasteur and Comvax manufacturer Merck—and has received honoraria for lectures and service on advisory board for these companies. Another author has been an investigator on clinical trials funded by Sanofi Pasteur and Merck, and has received honoraria for lectures and service on advisory boards for the companies.

GAITHERSBURG, MD. — A federal advisory panel has recommended that the immune modulator natalizumab be approved to treat moderate to severe Crohn disease under highly restrictive conditions.

Because of the serious risks associated with this agent, including progressive multifocal leukoencephalopathy (PML) and other opportunistic infections, the panel recommended that natalizumab use be restricted to those who have failed other treatments or cannot tolerate anti-tumor necrosis factor therapies.

At a joint meeting, the Food and Drug Administration's Gastrointestinal Drugs and Drug Safety and Risk Management advisory committees voted 12–3, with 2 abstentions, in favor of approving natalizumab for this indication. The FDA usually follows the recommendations of its advisory panels, which are not binding.

The chairman of the GI drugs panel, Dr. David B. Sachar, said that he supported approval for patients with moderate to severe Crohn who have evidence of ongoing inflammation, such as an elevated C-reactive protein (CRP) level, and “who have failed to achieve adequate sustained responses to safe and well-tolerated medications, steroids, and immunomodulators.” Anti-TNF therapies and immunomodulators should be discontinued before starting treatment, he said. Natalizumab should be discontinued if the patient has not responded in 3 months or if steroids cannot be discontinued within 6 months of starting treatment, added Dr. Sachar, director emeritus of the division of gastroenterology, Mount Sinai School of Medicine, New York.

Dr. Robert Levine, professor of medicine in the division of gastroenterology, State University of New York, Syracuse, said that while it was clear this drug was “no blockbuster,” he would support its availability with a new mechanism of action for this population, with a risk management plan that was as restrictive as possible.

Those voting against approval expressed concerns about the unknown long-term risks of natalizumab in Crohn patients.

Natalizumab, marketed as Tysabri by Elan Pharmaceuticals Inc. and Biogen Idec, is administered in a monthly infusion, and is approved as monotherapy for treating relapsing forms of multiple sclerosis. It is available through the TOUCH program, a risk management plan that was developed to address the risk of PML, a rare but usually fatal, progressive demyelinating CNS infection that was reported in three patients treated with natalizumab in trials. Two cases, one of which was fatal, were identified soon after natalizumab was initially approved to treat MS in November 2004. These cases prompted the manufacturer to take natalizumab off the market and suspend clinical trials in February 2005.

A fatal case of PML subsequently was identified in a 60-year-old man who had received a total of 8 months of natalizumab treatment in the Crohn disease trial; the man had a history of immunosuppressant use and lymphopenia. The TOUCH program was initiated when natalizumab was reintroduced to the U.S. market in June 2006.

PML is caused by activation of a human polyomavirus—the JC virus—which is latent in many healthy adults but can be activated in people who are immunosuppressed. The two MS patients with PML also were being treated with interferon beta-1a; when natalizumab was reintroduced, it was approved as monotherapy.

Components of the TOUCH program include a mandatory registry of patients and physicians, centralized distribution of the product, a monthly preinfusion checklist to screen patients for new or worsening symptoms that could indicate PML and use of immunosuppressants, and mandatory reporting of PML cases.

To date, no other PML cases have been identified in MS patients who have received natalizumab under the restricted program, and the risk of PML currently is estimated at about 1/1,000 patients treated with natalizumab for a mean of 18 months. The risk with longer treatment is not known.

Natalizumab was compared with placebo in two induction studies of 1,415 patients with moderately to severely active Crohn disease, and a 12-month maintenance study, which evaluated 300 mg of natalizumab administered intravenously every 4 weeks, the currently approved regimen for MS. In these trials, the beneficial effects over placebo were modest, and not as striking as in the MS studies. Patients were allowed to continue using 5-aminosalicylic acid, steroids, and immunosuppressants, but not anti-TNF therapy.

In the first induction study, the clinical response rate—a reduction in the Crohn's Disease Activity Index (CDAI) score of at least 70 from baseline—was not significantly different at 10 weeks between the 724 patients on natalizumab and the 181 patients on placebo (56% vs. 49%).

In a post hoc analysis of patients in the trial who had an elevated CRP, response rates were 58% among those on natalizumab vs. 45% among those on placebo, a significant difference.

In the second induction study of more than 500 patients, only those with elevated CRP levels were enrolled to determine whether the effectiveness of natalizumab was greater when inflammation was increased, as measured by an elevated CRP. At weeks 8 and 12, clinical response rates were significantly higher among those on natalizumab than placebo (48% vs. 32%), a statistically significant difference.

In the maintenance study that enrolled responders to natalizumab to placebo or natalizumab, response rates at 9 and 15 months were 61% and 54%, respectively, among those who continued on natalizumab vs. 28% and 20%, among those on placebo, significant differences.

No PML cases were identified in the studies. Adverse events included hypersensitivity reactions, at a rate of 3.5%. The malignancy rate was slightly higher for natalizumab vs. placebo (0.6% vs. 0.2%). Infections were slightly more common, including upper respiratory tract infections and herpes simplex infections, in natalizumab-treated patients. There were two cases of viral meningitis and one case of cytomegalovirus colitis, but none in placebo-treated patients in the 3-month trials.

The company has proposed a version of the TOUCH prescribing program adapted for Crohn disease patients, called “CD-TOUCH,” with the same goals but with modifications to accommodate differences in the treatment and management of patients with CD. One difference is the recommendation to stop treatment in patients who have had no response in 3 months and to eliminate corticosteroid use within 6 months of starting treatment.

As of July 2007, more than 8,600 patients had received treatment with natalizumab commercially, and more than 4,300 patients were receiving the drug in the European Union. In July, Elan and Biogen Idec announced that they were appealing a European Medicines Agency decision against approving natalizumab for patients with Crohn disease.

GAITHERSBURG, MD. — A federal advisory panel has recommended that the immune modulator natalizumab be approved to treat moderate to severe Crohn disease under highly restrictive conditions.

Because of the serious risks associated with this agent, including progressive multifocal leukoencephalopathy (PML) and other opportunistic infections, the panel recommended that natalizumab use be restricted to those who have failed other treatments or cannot tolerate anti-tumor necrosis factor therapies.

At a joint meeting, the Food and Drug Administration's Gastrointestinal Drugs and Drug Safety and Risk Management advisory committees voted 12–3, with 2 abstentions, in favor of approving natalizumab for this indication. The FDA usually follows the recommendations of its advisory panels, which are not binding.

The chairman of the GI drugs panel, Dr. David B. Sachar, said that he supported approval for patients with moderate to severe Crohn who have evidence of ongoing inflammation, such as an elevated C-reactive protein (CRP) level, and “who have failed to achieve adequate sustained responses to safe and well-tolerated medications, steroids, and immunomodulators.” Anti-TNF therapies and immunomodulators should be discontinued before starting treatment, he said. Natalizumab should be discontinued if the patient has not responded in 3 months or if steroids cannot be discontinued within 6 months of starting treatment, added Dr. Sachar, director emeritus of the division of gastroenterology, Mount Sinai School of Medicine, New York.

Dr. Robert Levine, professor of medicine in the division of gastroenterology, State University of New York, Syracuse, said that while it was clear this drug was “no blockbuster,” he would support its availability with a new mechanism of action for this population, with a risk management plan that was as restrictive as possible.

Those voting against approval expressed concerns about the unknown long-term risks of natalizumab in Crohn patients.

Natalizumab, marketed as Tysabri by Elan Pharmaceuticals Inc. and Biogen Idec, is administered in a monthly infusion, and is approved as monotherapy for treating relapsing forms of multiple sclerosis. It is available through the TOUCH program, a risk management plan that was developed to address the risk of PML, a rare but usually fatal, progressive demyelinating CNS infection that was reported in three patients treated with natalizumab in trials. Two cases, one of which was fatal, were identified soon after natalizumab was initially approved to treat MS in November 2004. These cases prompted the manufacturer to take natalizumab off the market and suspend clinical trials in February 2005.

A fatal case of PML subsequently was identified in a 60-year-old man who had received a total of 8 months of natalizumab treatment in the Crohn disease trial; the man had a history of immunosuppressant use and lymphopenia. The TOUCH program was initiated when natalizumab was reintroduced to the U.S. market in June 2006.

PML is caused by activation of a human polyomavirus—the JC virus—which is latent in many healthy adults but can be activated in people who are immunosuppressed. The two MS patients with PML also were being treated with interferon beta-1a; when natalizumab was reintroduced, it was approved as monotherapy.

Components of the TOUCH program include a mandatory registry of patients and physicians, centralized distribution of the product, a monthly preinfusion checklist to screen patients for new or worsening symptoms that could indicate PML and use of immunosuppressants, and mandatory reporting of PML cases.

To date, no other PML cases have been identified in MS patients who have received natalizumab under the restricted program, and the risk of PML currently is estimated at about 1/1,000 patients treated with natalizumab for a mean of 18 months. The risk with longer treatment is not known.

Natalizumab was compared with placebo in two induction studies of 1,415 patients with moderately to severely active Crohn disease, and a 12-month maintenance study, which evaluated 300 mg of natalizumab administered intravenously every 4 weeks, the currently approved regimen for MS. In these trials, the beneficial effects over placebo were modest, and not as striking as in the MS studies. Patients were allowed to continue using 5-aminosalicylic acid, steroids, and immunosuppressants, but not anti-TNF therapy.

In the first induction study, the clinical response rate—a reduction in the Crohn's Disease Activity Index (CDAI) score of at least 70 from baseline—was not significantly different at 10 weeks between the 724 patients on natalizumab and the 181 patients on placebo (56% vs. 49%).

In a post hoc analysis of patients in the trial who had an elevated CRP, response rates were 58% among those on natalizumab vs. 45% among those on placebo, a significant difference.

In the second induction study of more than 500 patients, only those with elevated CRP levels were enrolled to determine whether the effectiveness of natalizumab was greater when inflammation was increased, as measured by an elevated CRP. At weeks 8 and 12, clinical response rates were significantly higher among those on natalizumab than placebo (48% vs. 32%), a statistically significant difference.

In the maintenance study that enrolled responders to natalizumab to placebo or natalizumab, response rates at 9 and 15 months were 61% and 54%, respectively, among those who continued on natalizumab vs. 28% and 20%, among those on placebo, significant differences.

No PML cases were identified in the studies. Adverse events included hypersensitivity reactions, at a rate of 3.5%. The malignancy rate was slightly higher for natalizumab vs. placebo (0.6% vs. 0.2%). Infections were slightly more common, including upper respiratory tract infections and herpes simplex infections, in natalizumab-treated patients. There were two cases of viral meningitis and one case of cytomegalovirus colitis, but none in placebo-treated patients in the 3-month trials.

The company has proposed a version of the TOUCH prescribing program adapted for Crohn disease patients, called “CD-TOUCH,” with the same goals but with modifications to accommodate differences in the treatment and management of patients with CD. One difference is the recommendation to stop treatment in patients who have had no response in 3 months and to eliminate corticosteroid use within 6 months of starting treatment.

As of July 2007, more than 8,600 patients had received treatment with natalizumab commercially, and more than 4,300 patients were receiving the drug in the European Union. In July, Elan and Biogen Idec announced that they were appealing a European Medicines Agency decision against approving natalizumab for patients with Crohn disease.

GAITHERSBURG, MD. — A federal advisory panel has recommended that the immune modulator natalizumab be approved to treat moderate to severe Crohn disease under highly restrictive conditions.

Because of the serious risks associated with this agent, including progressive multifocal leukoencephalopathy (PML) and other opportunistic infections, the panel recommended that natalizumab use be restricted to those who have failed other treatments or cannot tolerate anti-tumor necrosis factor therapies.

At a joint meeting, the Food and Drug Administration's Gastrointestinal Drugs and Drug Safety and Risk Management advisory committees voted 12–3, with 2 abstentions, in favor of approving natalizumab for this indication. The FDA usually follows the recommendations of its advisory panels, which are not binding.

The chairman of the GI drugs panel, Dr. David B. Sachar, said that he supported approval for patients with moderate to severe Crohn who have evidence of ongoing inflammation, such as an elevated C-reactive protein (CRP) level, and “who have failed to achieve adequate sustained responses to safe and well-tolerated medications, steroids, and immunomodulators.” Anti-TNF therapies and immunomodulators should be discontinued before starting treatment, he said. Natalizumab should be discontinued if the patient has not responded in 3 months or if steroids cannot be discontinued within 6 months of starting treatment, added Dr. Sachar, director emeritus of the division of gastroenterology, Mount Sinai School of Medicine, New York.

Dr. Robert Levine, professor of medicine in the division of gastroenterology, State University of New York, Syracuse, said that while it was clear this drug was “no blockbuster,” he would support its availability with a new mechanism of action for this population, with a risk management plan that was as restrictive as possible.

Those voting against approval expressed concerns about the unknown long-term risks of natalizumab in Crohn patients.

Natalizumab, marketed as Tysabri by Elan Pharmaceuticals Inc. and Biogen Idec, is administered in a monthly infusion, and is approved as monotherapy for treating relapsing forms of multiple sclerosis. It is available through the TOUCH program, a risk management plan that was developed to address the risk of PML, a rare but usually fatal, progressive demyelinating CNS infection that was reported in three patients treated with natalizumab in trials. Two cases, one of which was fatal, were identified soon after natalizumab was initially approved to treat MS in November 2004. These cases prompted the manufacturer to take natalizumab off the market and suspend clinical trials in February 2005.

A fatal case of PML subsequently was identified in a 60-year-old man who had received a total of 8 months of natalizumab treatment in the Crohn disease trial; the man had a history of immunosuppressant use and lymphopenia. The TOUCH program was initiated when natalizumab was reintroduced to the U.S. market in June 2006.

PML is caused by activation of a human polyomavirus—the JC virus—which is latent in many healthy adults but can be activated in people who are immunosuppressed. The two MS patients with PML also were being treated with interferon beta-1a; when natalizumab was reintroduced, it was approved as monotherapy.

Components of the TOUCH program include a mandatory registry of patients and physicians, centralized distribution of the product, a monthly preinfusion checklist to screen patients for new or worsening symptoms that could indicate PML and use of immunosuppressants, and mandatory reporting of PML cases.

To date, no other PML cases have been identified in MS patients who have received natalizumab under the restricted program, and the risk of PML currently is estimated at about 1/1,000 patients treated with natalizumab for a mean of 18 months. The risk with longer treatment is not known.

Natalizumab was compared with placebo in two induction studies of 1,415 patients with moderately to severely active Crohn disease, and a 12-month maintenance study, which evaluated 300 mg of natalizumab administered intravenously every 4 weeks, the currently approved regimen for MS. In these trials, the beneficial effects over placebo were modest, and not as striking as in the MS studies. Patients were allowed to continue using 5-aminosalicylic acid, steroids, and immunosuppressants, but not anti-TNF therapy.

In the first induction study, the clinical response rate—a reduction in the Crohn's Disease Activity Index (CDAI) score of at least 70 from baseline—was not significantly different at 10 weeks between the 724 patients on natalizumab and the 181 patients on placebo (56% vs. 49%).

In a post hoc analysis of patients in the trial who had an elevated CRP, response rates were 58% among those on natalizumab vs. 45% among those on placebo, a significant difference.

In the second induction study of more than 500 patients, only those with elevated CRP levels were enrolled to determine whether the effectiveness of natalizumab was greater when inflammation was increased, as measured by an elevated CRP. At weeks 8 and 12, clinical response rates were significantly higher among those on natalizumab than placebo (48% vs. 32%), a statistically significant difference.

In the maintenance study that enrolled responders to natalizumab to placebo or natalizumab, response rates at 9 and 15 months were 61% and 54%, respectively, among those who continued on natalizumab vs. 28% and 20%, among those on placebo, significant differences.

No PML cases were identified in the studies. Adverse events included hypersensitivity reactions, at a rate of 3.5%. The malignancy rate was slightly higher for natalizumab vs. placebo (0.6% vs. 0.2%). Infections were slightly more common, including upper respiratory tract infections and herpes simplex infections, in natalizumab-treated patients. There were two cases of viral meningitis and one case of cytomegalovirus colitis, but none in placebo-treated patients in the 3-month trials.

The company has proposed a version of the TOUCH prescribing program adapted for Crohn disease patients, called “CD-TOUCH,” with the same goals but with modifications to accommodate differences in the treatment and management of patients with CD. One difference is the recommendation to stop treatment in patients who have had no response in 3 months and to eliminate corticosteroid use within 6 months of starting treatment.

As of July 2007, more than 8,600 patients had received treatment with natalizumab commercially, and more than 4,300 patients were receiving the drug in the European Union. In July, Elan and Biogen Idec announced that they were appealing a European Medicines Agency decision against approving natalizumab for patients with Crohn disease.