Elizabeth Mechcatie

Diabetes management is becoming less “glucocentric” than it used to be, according to Dr. Helena W. Rodbard.

Dr. Rodbard is the chairperson of the task force that wrote the new clinical practice guidelines on the management of diabetes issued by the American Association of Clinical Endocrinologists. Instead of talking only about how to keep blood glucose at the ideal level, the new guidelines provide more emphasis on lifestyle—in terms of prevention of diabetes—as well as the importance of managing blood pressure and lipids, she said in an interview.

In addition, previous guidelines did not include much information on diabetes complications, particularly microvascular complications, and diabetes management in the hospital setting, both topics of separate sections of the new guidelines. There are also sections on nutrition, screening and diagnosis, glycemic management in type 1 and type 2 diabetes, diabetes and pregnancy, and patient safety in diabetes care.

The guidelines were published in a supplement to Endocrine Practice that was mailed to AACE members and journal subscribers in July (Endocr. Pract. 2007;13[Suppl 1]), and are a result of almost 3 years of work by the task force, which was made up of endocrinologists specializing in diabetes, Dr. Rodbard said.

The final recommendations in the guidelines represent a consensus among the task force members, and were also approved by the AACE board of directors.

These guidelines are distinct from the “Road Maps for the Prevention and Treatment of Type 2 Diabetes” recently released by AACE. The road maps are not guidelines, but instead provide specific treatment algorithms and focus more on glycemic control.

The guidelines include a section on the medical management of diabetes, which contains reviews of the different drugs available, their indications for use, their advantages and disadvantages, and their expected impact on reducing in HbA_1c levels.

They do not specifically recommend any one drug or class of drugs as a first-line treatment, but instead, they focus on the importance of individualizing treatment, Dr. Rodbard explained.

“We don't have a cookbook approach because every patient is different, and we list the different medications, the indications for each drug, and which subset of patients can benefit from one versus the other medication,” she said.

That approach contrasts with the American Diabetes Association, which last year endorsed a consensus algorithm that recommended metformin along with lifestyle interventions for newly diagnosed type 2 diabetes.

“That may be appropriate for many, perhaps most patients with type 2 diabetes, but definitely not for everybody,” Dr. Rodbard noted. “It is up to the judgement of the physician to make a decision about whether metformin would or would not be the right drug for an individual patient.”

The task force was able to add a statement close to the publication date regarding a recent meta-analysis reporting an increased risk of myocardial infarction associated with rosiglitazone therapy (N. Engl. J. Med. 2007 [Epub doi:10.1056/NEJMoa072761]). Despite the controversy over the meta-analysis and the unresolved issues, “we felt we had to say something about it, although we tried to keep a very balanced opinion in that regard and are not recommending that patients stop the medication,” Dr. Rodbard said.

The statement, which appears in the glycemic management section, says that “definitive resolution regarding the magnitude and statistical and clinical significance of these findings” will require further analyses, including the results of an ongoing phase III study expected to be completed in 2009.

The guidelines also list peripheral fractures in women among the adverse effects of thiazolidinediones (TZDs), a reference to findings showing an increased rate of peripheral fractures in women taking either rosiglitazone or pioglitazone (“Second TZD Connected to Excess Fractures in Women,” April 2007, p. 1).

In the section on glycemic management, AACE recommends a glycemic target that includes an HbA_1c equal to or below 6.5%, a fasting plasma glucose concentration below 110 mg/dL, and a 2-hour postprandial glucose concentration below 140 mg/dL, values that AACE has advocated in the past. The glycemic goals in the guidelines are consistent with previous AACE consensus conferences and a position statement regarding these targets, said Dr. Paul S. Jellinger, a task force member and a past president of both AACE and the American College of Endocrinology, who is in private practice in Hollywood, Fla.

The guidelines are a “very nice blend of evidence-based and evidence-ranked statements, which also reflect the extensive clinical experience of the task force members,” he added. Written with the clinician in mind, “we expect this will be a source of clinically useful information” for any clinician involved in the care of people with diabetes, he said.

AACE last issued diabetes guidelines in 2002. There are plans to release an update of the guidelines next year as new data become available, said Dr. Rodbard. A section on type 2 diabetes in the pediatric population may be included in the updated guidelines, because teenagers are the fastest-growing segment of type 2 diabetes patients.

The guidelines are available online at www.aace.com/pub/pdf/guidelines/DMGuidelines2007.pdf

Diabetes management is becoming less “glucocentric” than it used to be, according to Dr. Helena W. Rodbard.

Dr. Rodbard is the chairperson of the task force that wrote the new clinical practice guidelines on the management of diabetes issued by the American Association of Clinical Endocrinologists. Instead of talking only about how to keep blood glucose at the ideal level, the new guidelines provide more emphasis on lifestyle—in terms of prevention of diabetes—as well as the importance of managing blood pressure and lipids, she said in an interview.

In addition, previous guidelines did not include much information on diabetes complications, particularly microvascular complications, and diabetes management in the hospital setting, both topics of separate sections of the new guidelines. There are also sections on nutrition, screening and diagnosis, glycemic management in type 1 and type 2 diabetes, diabetes and pregnancy, and patient safety in diabetes care.

The guidelines were published in a supplement to Endocrine Practice that was mailed to AACE members and journal subscribers in July (Endocr. Pract. 2007;13[Suppl 1]), and are a result of almost 3 years of work by the task force, which was made up of endocrinologists specializing in diabetes, Dr. Rodbard said.

The final recommendations in the guidelines represent a consensus among the task force members, and were also approved by the AACE board of directors.

These guidelines are distinct from the “Road Maps for the Prevention and Treatment of Type 2 Diabetes” recently released by AACE. The road maps are not guidelines, but instead provide specific treatment algorithms and focus more on glycemic control.

The guidelines include a section on the medical management of diabetes, which contains reviews of the different drugs available, their indications for use, their advantages and disadvantages, and their expected impact on reducing in HbA_1c levels.

They do not specifically recommend any one drug or class of drugs as a first-line treatment, but instead, they focus on the importance of individualizing treatment, Dr. Rodbard explained.

“We don't have a cookbook approach because every patient is different, and we list the different medications, the indications for each drug, and which subset of patients can benefit from one versus the other medication,” she said.

That approach contrasts with the American Diabetes Association, which last year endorsed a consensus algorithm that recommended metformin along with lifestyle interventions for newly diagnosed type 2 diabetes.

“That may be appropriate for many, perhaps most patients with type 2 diabetes, but definitely not for everybody,” Dr. Rodbard noted. “It is up to the judgement of the physician to make a decision about whether metformin would or would not be the right drug for an individual patient.”

The task force was able to add a statement close to the publication date regarding a recent meta-analysis reporting an increased risk of myocardial infarction associated with rosiglitazone therapy (N. Engl. J. Med. 2007 [Epub doi:10.1056/NEJMoa072761]). Despite the controversy over the meta-analysis and the unresolved issues, “we felt we had to say something about it, although we tried to keep a very balanced opinion in that regard and are not recommending that patients stop the medication,” Dr. Rodbard said.

The statement, which appears in the glycemic management section, says that “definitive resolution regarding the magnitude and statistical and clinical significance of these findings” will require further analyses, including the results of an ongoing phase III study expected to be completed in 2009.

The guidelines also list peripheral fractures in women among the adverse effects of thiazolidinediones (TZDs), a reference to findings showing an increased rate of peripheral fractures in women taking either rosiglitazone or pioglitazone (“Second TZD Connected to Excess Fractures in Women,” April 2007, p. 1).

In the section on glycemic management, AACE recommends a glycemic target that includes an HbA_1c equal to or below 6.5%, a fasting plasma glucose concentration below 110 mg/dL, and a 2-hour postprandial glucose concentration below 140 mg/dL, values that AACE has advocated in the past. The glycemic goals in the guidelines are consistent with previous AACE consensus conferences and a position statement regarding these targets, said Dr. Paul S. Jellinger, a task force member and a past president of both AACE and the American College of Endocrinology, who is in private practice in Hollywood, Fla.

The guidelines are a “very nice blend of evidence-based and evidence-ranked statements, which also reflect the extensive clinical experience of the task force members,” he added. Written with the clinician in mind, “we expect this will be a source of clinically useful information” for any clinician involved in the care of people with diabetes, he said.

AACE last issued diabetes guidelines in 2002. There are plans to release an update of the guidelines next year as new data become available, said Dr. Rodbard. A section on type 2 diabetes in the pediatric population may be included in the updated guidelines, because teenagers are the fastest-growing segment of type 2 diabetes patients.

The guidelines are available online at www.aace.com/pub/pdf/guidelines/DMGuidelines2007.pdf

Diabetes management is becoming less “glucocentric” than it used to be, according to Dr. Helena W. Rodbard.

Dr. Rodbard is the chairperson of the task force that wrote the new clinical practice guidelines on the management of diabetes issued by the American Association of Clinical Endocrinologists. Instead of talking only about how to keep blood glucose at the ideal level, the new guidelines provide more emphasis on lifestyle—in terms of prevention of diabetes—as well as the importance of managing blood pressure and lipids, she said in an interview.

In addition, previous guidelines did not include much information on diabetes complications, particularly microvascular complications, and diabetes management in the hospital setting, both topics of separate sections of the new guidelines. There are also sections on nutrition, screening and diagnosis, glycemic management in type 1 and type 2 diabetes, diabetes and pregnancy, and patient safety in diabetes care.

The guidelines were published in a supplement to Endocrine Practice that was mailed to AACE members and journal subscribers in July (Endocr. Pract. 2007;13[Suppl 1]), and are a result of almost 3 years of work by the task force, which was made up of endocrinologists specializing in diabetes, Dr. Rodbard said.

The final recommendations in the guidelines represent a consensus among the task force members, and were also approved by the AACE board of directors.

These guidelines are distinct from the “Road Maps for the Prevention and Treatment of Type 2 Diabetes” recently released by AACE. The road maps are not guidelines, but instead provide specific treatment algorithms and focus more on glycemic control.

The guidelines include a section on the medical management of diabetes, which contains reviews of the different drugs available, their indications for use, their advantages and disadvantages, and their expected impact on reducing in HbA_1c levels.

They do not specifically recommend any one drug or class of drugs as a first-line treatment, but instead, they focus on the importance of individualizing treatment, Dr. Rodbard explained.

“We don't have a cookbook approach because every patient is different, and we list the different medications, the indications for each drug, and which subset of patients can benefit from one versus the other medication,” she said.

That approach contrasts with the American Diabetes Association, which last year endorsed a consensus algorithm that recommended metformin along with lifestyle interventions for newly diagnosed type 2 diabetes.

“That may be appropriate for many, perhaps most patients with type 2 diabetes, but definitely not for everybody,” Dr. Rodbard noted. “It is up to the judgement of the physician to make a decision about whether metformin would or would not be the right drug for an individual patient.”

The task force was able to add a statement close to the publication date regarding a recent meta-analysis reporting an increased risk of myocardial infarction associated with rosiglitazone therapy (N. Engl. J. Med. 2007 [Epub doi:10.1056/NEJMoa072761]). Despite the controversy over the meta-analysis and the unresolved issues, “we felt we had to say something about it, although we tried to keep a very balanced opinion in that regard and are not recommending that patients stop the medication,” Dr. Rodbard said.

The statement, which appears in the glycemic management section, says that “definitive resolution regarding the magnitude and statistical and clinical significance of these findings” will require further analyses, including the results of an ongoing phase III study expected to be completed in 2009.

The guidelines also list peripheral fractures in women among the adverse effects of thiazolidinediones (TZDs), a reference to findings showing an increased rate of peripheral fractures in women taking either rosiglitazone or pioglitazone (“Second TZD Connected to Excess Fractures in Women,” April 2007, p. 1).

In the section on glycemic management, AACE recommends a glycemic target that includes an HbA_1c equal to or below 6.5%, a fasting plasma glucose concentration below 110 mg/dL, and a 2-hour postprandial glucose concentration below 140 mg/dL, values that AACE has advocated in the past. The glycemic goals in the guidelines are consistent with previous AACE consensus conferences and a position statement regarding these targets, said Dr. Paul S. Jellinger, a task force member and a past president of both AACE and the American College of Endocrinology, who is in private practice in Hollywood, Fla.

The guidelines are a “very nice blend of evidence-based and evidence-ranked statements, which also reflect the extensive clinical experience of the task force members,” he added. Written with the clinician in mind, “we expect this will be a source of clinically useful information” for any clinician involved in the care of people with diabetes, he said.

AACE last issued diabetes guidelines in 2002. There are plans to release an update of the guidelines next year as new data become available, said Dr. Rodbard. A section on type 2 diabetes in the pediatric population may be included in the updated guidelines, because teenagers are the fastest-growing segment of type 2 diabetes patients.

The guidelines are available online at www.aace.com/pub/pdf/guidelines/DMGuidelines2007.pdf

Early treatment with interferon-beta in patients who have experienced a clinical event suggestive of multiple sclerosis can delay disability progression, said Dr. Ludwig Kappos of University Hospital, Basel (Switzerland).

The study, conducted in several European countries, was the follow-up of the initial phase of the BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) study of 468 people (mean age 30 years) with a first event suggestive of MS and at least two clinically silent MRI lesions. In the first 2-year phase of the study, 292 patients were randomized to start treatment with interferon beta-1b (250 mcg subcutaneously every other day) within 60 days of developing the event, and 176 received placebo. The follow-up study analyzed patients 3 years after the beginning of the 2-year placebo-controlled phase and enrolled nearly 90%—418—of the patients who had completed that phase; 378 chose to take interferon-beta starting at 2 years, and 392 completed the 3-year follow-up. At that time, 16% of patients in the early-treatment group had confirmed progression on the Expanded Disability Status Scale (EDSS), versus 24% of patients in the delayed treatment group. Treatment was tied to a 40% reduced risk. The number needed to treat early to avoid one additional confirmed case of EDSS progression was almost 12, the authors wrote (Lancet 2007;370:389–97).

Also at 3 years, 37% of patients in the early-therapy group developed conversion to clinically definite MS (CDMS) vs. 51% of those who received delayed treatment, a 41% risk reduction. The number needed to treat early to avoid one additional CDMS conversion was seven. Over the 3 years, patient-reported functional assessment scale scores were high and stable.

The early-treatment group was exposed to interferon-beta for a median of 1,080 days over 3 years, versus a median of 364 days in the delayed treatment group.

The impact on the EDSS 3 years after the onset of the first MS-type event indicates that “a delay of such treatment by, essentially, just one event, even at this early stage of the disease, has an effect on later accumulation of disability,” Dr. Kappos and his associates wrote.

Adverse events were typical of the side effect profile; flulike symptoms and injection site reactions were reported in about half of all patients.

The authors noted that in three multicenter, placebo-controlled studies, CDMS was delayed in patients who received treatment with interferon-beta for a first episode of neurologic symptoms that were highly suggestive of MS. But to date, they said, there had been no controlled evidence that early initiation of treatment with interferon-beta affects the development of confirmed disability, compared with delaying treatment. A 5-year follow-up of the participants is planned.

In an accompanying editorial, Dr. Sean J. Pittock of the departments of neurology and laboratory medicine and pathology at the Mayo Clinic, Rochester, Minn., said that though the study presents the first evidence of interferon beta-1b's benefit, the magnitude of benefit, though statistically significant, is clinically small (Lancet 2007;370:363–4).

Interferon beta-1b is marketed in the U.S. by Bayer HealthCare Pharmaceuticals Inc. as Betaseron, with approval for treating relapsing forms of MS to reduce the frequency of clinical exacerbations. The approved label includes the statement that patients with MS “in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with” MS.

Dr. Pittock disclosed no conflict of interest. Some of the study's authors were from Bayer Schering Pharma AG. The disclosure statement for the other authors, including Dr. Kappos, listed several as having received research support and having served as consultants to Bayer Schering and other pharmaceutical companies.

Early treatment with interferon-beta in patients who have experienced a clinical event suggestive of multiple sclerosis can delay disability progression, said Dr. Ludwig Kappos of University Hospital, Basel (Switzerland).

The study, conducted in several European countries, was the follow-up of the initial phase of the BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) study of 468 people (mean age 30 years) with a first event suggestive of MS and at least two clinically silent MRI lesions. In the first 2-year phase of the study, 292 patients were randomized to start treatment with interferon beta-1b (250 mcg subcutaneously every other day) within 60 days of developing the event, and 176 received placebo. The follow-up study analyzed patients 3 years after the beginning of the 2-year placebo-controlled phase and enrolled nearly 90%—418—of the patients who had completed that phase; 378 chose to take interferon-beta starting at 2 years, and 392 completed the 3-year follow-up. At that time, 16% of patients in the early-treatment group had confirmed progression on the Expanded Disability Status Scale (EDSS), versus 24% of patients in the delayed treatment group. Treatment was tied to a 40% reduced risk. The number needed to treat early to avoid one additional confirmed case of EDSS progression was almost 12, the authors wrote (Lancet 2007;370:389–97).

Also at 3 years, 37% of patients in the early-therapy group developed conversion to clinically definite MS (CDMS) vs. 51% of those who received delayed treatment, a 41% risk reduction. The number needed to treat early to avoid one additional CDMS conversion was seven. Over the 3 years, patient-reported functional assessment scale scores were high and stable.

The early-treatment group was exposed to interferon-beta for a median of 1,080 days over 3 years, versus a median of 364 days in the delayed treatment group.

The impact on the EDSS 3 years after the onset of the first MS-type event indicates that “a delay of such treatment by, essentially, just one event, even at this early stage of the disease, has an effect on later accumulation of disability,” Dr. Kappos and his associates wrote.

Adverse events were typical of the side effect profile; flulike symptoms and injection site reactions were reported in about half of all patients.

The authors noted that in three multicenter, placebo-controlled studies, CDMS was delayed in patients who received treatment with interferon-beta for a first episode of neurologic symptoms that were highly suggestive of MS. But to date, they said, there had been no controlled evidence that early initiation of treatment with interferon-beta affects the development of confirmed disability, compared with delaying treatment. A 5-year follow-up of the participants is planned.

In an accompanying editorial, Dr. Sean J. Pittock of the departments of neurology and laboratory medicine and pathology at the Mayo Clinic, Rochester, Minn., said that though the study presents the first evidence of interferon beta-1b's benefit, the magnitude of benefit, though statistically significant, is clinically small (Lancet 2007;370:363–4).

Interferon beta-1b is marketed in the U.S. by Bayer HealthCare Pharmaceuticals Inc. as Betaseron, with approval for treating relapsing forms of MS to reduce the frequency of clinical exacerbations. The approved label includes the statement that patients with MS “in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with” MS.

Dr. Pittock disclosed no conflict of interest. Some of the study's authors were from Bayer Schering Pharma AG. The disclosure statement for the other authors, including Dr. Kappos, listed several as having received research support and having served as consultants to Bayer Schering and other pharmaceutical companies.

Early treatment with interferon-beta in patients who have experienced a clinical event suggestive of multiple sclerosis can delay disability progression, said Dr. Ludwig Kappos of University Hospital, Basel (Switzerland).

The study, conducted in several European countries, was the follow-up of the initial phase of the BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) study of 468 people (mean age 30 years) with a first event suggestive of MS and at least two clinically silent MRI lesions. In the first 2-year phase of the study, 292 patients were randomized to start treatment with interferon beta-1b (250 mcg subcutaneously every other day) within 60 days of developing the event, and 176 received placebo. The follow-up study analyzed patients 3 years after the beginning of the 2-year placebo-controlled phase and enrolled nearly 90%—418—of the patients who had completed that phase; 378 chose to take interferon-beta starting at 2 years, and 392 completed the 3-year follow-up. At that time, 16% of patients in the early-treatment group had confirmed progression on the Expanded Disability Status Scale (EDSS), versus 24% of patients in the delayed treatment group. Treatment was tied to a 40% reduced risk. The number needed to treat early to avoid one additional confirmed case of EDSS progression was almost 12, the authors wrote (Lancet 2007;370:389–97).

Also at 3 years, 37% of patients in the early-therapy group developed conversion to clinically definite MS (CDMS) vs. 51% of those who received delayed treatment, a 41% risk reduction. The number needed to treat early to avoid one additional CDMS conversion was seven. Over the 3 years, patient-reported functional assessment scale scores were high and stable.

The early-treatment group was exposed to interferon-beta for a median of 1,080 days over 3 years, versus a median of 364 days in the delayed treatment group.

The impact on the EDSS 3 years after the onset of the first MS-type event indicates that “a delay of such treatment by, essentially, just one event, even at this early stage of the disease, has an effect on later accumulation of disability,” Dr. Kappos and his associates wrote.

Adverse events were typical of the side effect profile; flulike symptoms and injection site reactions were reported in about half of all patients.

The authors noted that in three multicenter, placebo-controlled studies, CDMS was delayed in patients who received treatment with interferon-beta for a first episode of neurologic symptoms that were highly suggestive of MS. But to date, they said, there had been no controlled evidence that early initiation of treatment with interferon-beta affects the development of confirmed disability, compared with delaying treatment. A 5-year follow-up of the participants is planned.

In an accompanying editorial, Dr. Sean J. Pittock of the departments of neurology and laboratory medicine and pathology at the Mayo Clinic, Rochester, Minn., said that though the study presents the first evidence of interferon beta-1b's benefit, the magnitude of benefit, though statistically significant, is clinically small (Lancet 2007;370:363–4).

Interferon beta-1b is marketed in the U.S. by Bayer HealthCare Pharmaceuticals Inc. as Betaseron, with approval for treating relapsing forms of MS to reduce the frequency of clinical exacerbations. The approved label includes the statement that patients with MS “in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with” MS.

Dr. Pittock disclosed no conflict of interest. Some of the study's authors were from Bayer Schering Pharma AG. The disclosure statement for the other authors, including Dr. Kappos, listed several as having received research support and having served as consultants to Bayer Schering and other pharmaceutical companies.

www.fda.gov/medwatch/safety/2007/safety07.htm#Rocephinwww.fda.gov/medwatch

Fatal cases of calcium-ceftriaxone precipitates in the lungs and kidneys of both term and premature newborns have prompted a warning and a new contraindication regarding concomitant use of the intravenous antibiotic ceftriaxone with calcium or calcium-containing solutions or products.

Last month, the Food and Drug Administration posted an alert on its MedWatch Web site informing health care professionals that ceftriaxone sodium for injection (Rocephin), “must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines.”

In addition, calcium-containing solutions or products should not be administered within 48 hours of the last administration of ceftriaxone, according to the FDA. This information is included in a “dear healthcare professional” letter issued by the manufacturer, Roche.

The FDA alert and Roche letter also emphasized that IV ceftriaxone should not be used to treat hyperbilirubinemic neonates, especially those who are premature. The letter cites in vitro studies that have shown that ceftriaxone “can displace bilirubin from its binding to serum albumin,” which can result in bilirubin encephalopathy in this population. Related information had been included in the pediatric use section of the prescribing information, but is now included in the contraindications section to “more prominently reinforce” this information, according to the letter.

The contraindications section also includes the statement that ceftriaxone “should not be administered concurrently with calcium-containing solutions or products in newborns because of the risk of precipitation of ceftriaxone-calcium salts.”

The Roche letter describes postmarketing reports of “isolated neonatal deaths” that were associated with calcium-ceftriaxone precipitates in the lungs and kidneys. In some of the cases, ceftriaxone and the calcium-containing solutions or medications had been administered by different routes and at different times.

Particulates also can form when diluents that contain calcium, such as Ringer's solution or Hartmann's solution, are used to reconstitute ceftriaxone for injection, according to the letter.

The contraindications, warnings, precautions, adverse reactions, and dosage and administration sections of the Rocephin label have been updated to reflect these revised recommendations. For more information, Roche can be contacted at 800-526-6367.

The approved indications for ceftriaxone include treatment of lower respiratory tract infections, skin and skin structure infections, urinary tract infections, intra-abdominal infections, acute bacterial otitis media when caused by susceptible organisms, and surgical prophylaxis.

www.fda.gov/medwatch/safety/2007/safety07.htm#Rocephinwww.fda.gov/medwatch

Fatal cases of calcium-ceftriaxone precipitates in the lungs and kidneys of both term and premature newborns have prompted a warning and a new contraindication regarding concomitant use of the intravenous antibiotic ceftriaxone with calcium or calcium-containing solutions or products.

Last month, the Food and Drug Administration posted an alert on its MedWatch Web site informing health care professionals that ceftriaxone sodium for injection (Rocephin), “must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines.”

In addition, calcium-containing solutions or products should not be administered within 48 hours of the last administration of ceftriaxone, according to the FDA. This information is included in a “dear healthcare professional” letter issued by the manufacturer, Roche.

The FDA alert and Roche letter also emphasized that IV ceftriaxone should not be used to treat hyperbilirubinemic neonates, especially those who are premature. The letter cites in vitro studies that have shown that ceftriaxone “can displace bilirubin from its binding to serum albumin,” which can result in bilirubin encephalopathy in this population. Related information had been included in the pediatric use section of the prescribing information, but is now included in the contraindications section to “more prominently reinforce” this information, according to the letter.

The contraindications section also includes the statement that ceftriaxone “should not be administered concurrently with calcium-containing solutions or products in newborns because of the risk of precipitation of ceftriaxone-calcium salts.”

The Roche letter describes postmarketing reports of “isolated neonatal deaths” that were associated with calcium-ceftriaxone precipitates in the lungs and kidneys. In some of the cases, ceftriaxone and the calcium-containing solutions or medications had been administered by different routes and at different times.

Particulates also can form when diluents that contain calcium, such as Ringer's solution or Hartmann's solution, are used to reconstitute ceftriaxone for injection, according to the letter.

The contraindications, warnings, precautions, adverse reactions, and dosage and administration sections of the Rocephin label have been updated to reflect these revised recommendations. For more information, Roche can be contacted at 800-526-6367.

The approved indications for ceftriaxone include treatment of lower respiratory tract infections, skin and skin structure infections, urinary tract infections, intra-abdominal infections, acute bacterial otitis media when caused by susceptible organisms, and surgical prophylaxis.

www.fda.gov/medwatch/safety/2007/safety07.htm#Rocephinwww.fda.gov/medwatch

Fatal cases of calcium-ceftriaxone precipitates in the lungs and kidneys of both term and premature newborns have prompted a warning and a new contraindication regarding concomitant use of the intravenous antibiotic ceftriaxone with calcium or calcium-containing solutions or products.

Last month, the Food and Drug Administration posted an alert on its MedWatch Web site informing health care professionals that ceftriaxone sodium for injection (Rocephin), “must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines.”

In addition, calcium-containing solutions or products should not be administered within 48 hours of the last administration of ceftriaxone, according to the FDA. This information is included in a “dear healthcare professional” letter issued by the manufacturer, Roche.

The FDA alert and Roche letter also emphasized that IV ceftriaxone should not be used to treat hyperbilirubinemic neonates, especially those who are premature. The letter cites in vitro studies that have shown that ceftriaxone “can displace bilirubin from its binding to serum albumin,” which can result in bilirubin encephalopathy in this population. Related information had been included in the pediatric use section of the prescribing information, but is now included in the contraindications section to “more prominently reinforce” this information, according to the letter.

The contraindications section also includes the statement that ceftriaxone “should not be administered concurrently with calcium-containing solutions or products in newborns because of the risk of precipitation of ceftriaxone-calcium salts.”

The Roche letter describes postmarketing reports of “isolated neonatal deaths” that were associated with calcium-ceftriaxone precipitates in the lungs and kidneys. In some of the cases, ceftriaxone and the calcium-containing solutions or medications had been administered by different routes and at different times.

Particulates also can form when diluents that contain calcium, such as Ringer's solution or Hartmann's solution, are used to reconstitute ceftriaxone for injection, according to the letter.

The contraindications, warnings, precautions, adverse reactions, and dosage and administration sections of the Rocephin label have been updated to reflect these revised recommendations. For more information, Roche can be contacted at 800-526-6367.

The approved indications for ceftriaxone include treatment of lower respiratory tract infections, skin and skin structure infections, urinary tract infections, intra-abdominal infections, acute bacterial otitis media when caused by susceptible organisms, and surgical prophylaxis.

Pregabalin has become the first drug to win approval by the Food and Drug Administration for the management of fibromyalgia.

The FDA based the approval on two double-blind, controlled trials of approximately 1,800 patients. Data from the studies have shown that patients with fibromyalgia “have decreased pain after taking [pregabalin], but, the mechanism by which [pregabalin] produces such an effect is unknown,” according to an agency-issued statement.

In the clinical trials of patients with fibromyalgia, those on pregabalin (Lyrica) had “rapid and sustained improvements in pain,” compared with those on placebo, and “reported feeling better and improvements in physical function,” according to a statement issued by Pfizer, which manufactures pregabalin. The same statement explains that the drug's mechanism of action for fibromyalgia is not known, but states that patients with fibromyalgia may be more sensitive than normal to stimuli that are not usually painful, and that pregabalin may reduce the degree of pain experienced by patients with fibromyalgia by binding to a specific protein within “overexcited nerve cells.”

The approval “marks an important advance, and provides a reason for optimism for the many patients who will receive pain relief” with pregabalin, Dr. Steven Galson, the director of the FDA's Center for Drug Evaluation and Research said in the FDA statement. He added, however, that consumers should understand that some patients in trials did not benefit from the drug, and that “we still have more progress to make for treatment of this disorder.”

The two studies enrolled patients diagnosed with fibromyalgia using American College of Rheumatology (ACR) criteria, which are a history of widespread pain for 3 months and pain present at 11 or more of the 18 specific tender point sites, according to the revised prescribing information for pregabalin. The two studies–a 14-week double-blind placebo-controlled study and a 6-month randomized withdrawal study–found that treatment was associated with a reduction in pain by visual analog scale and improvements based on a patient global assessment and on the Fibromyalgia Impact Questionnaire.

In the 14-week study, some patients experienced reductions in pain during the first week of treatment, which continued throughout the study. Nearly 70% of those on a total daily dose of 300 mg of pregabalin, and 78% of those on a total daily dose of 450 mg experienced any improvement on the patient global impression of change scale, compared with 48% of those on placebo. The total daily dose of 600 mg was not more effective than the lower doses, and there was evidence of dose-related side effects.

The daily dose should be administered in two divided doses per day, starting at a total daily dose of 150 mg/day, which may be increased to 300 mg/day, within 1 week; the maximum dose is 450 mg/day, according to the prescribing information.

The most common side effects in the trials were mild to moderate dizziness and sleepiness, blurred vision, weight gain, dry mouth, and swelling of the hands and feet also were also reported. Side effects appeared to be dose related, according to the FDA. Patients should talk to their physicians or other health care providers about whether pregabalin–which can impair motor function, concentration, and attention–can affect their ability to drive, the FDA advised. Pfizer has agreed to conduct a study of pregabalin in children and another in women who are breast-feeding.

Pregabalin, a centrally acting drug, was first approved in 2004 for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia, and for the adjunctive therapy for adult patients with partial onset seizures. It is taken orally in capsule form.

Pregabalin has become the first drug to win approval by the Food and Drug Administration for the management of fibromyalgia.

The FDA based the approval on two double-blind, controlled trials of approximately 1,800 patients. Data from the studies have shown that patients with fibromyalgia “have decreased pain after taking [pregabalin], but, the mechanism by which [pregabalin] produces such an effect is unknown,” according to an agency-issued statement.

In the clinical trials of patients with fibromyalgia, those on pregabalin (Lyrica) had “rapid and sustained improvements in pain,” compared with those on placebo, and “reported feeling better and improvements in physical function,” according to a statement issued by Pfizer, which manufactures pregabalin. The same statement explains that the drug's mechanism of action for fibromyalgia is not known, but states that patients with fibromyalgia may be more sensitive than normal to stimuli that are not usually painful, and that pregabalin may reduce the degree of pain experienced by patients with fibromyalgia by binding to a specific protein within “overexcited nerve cells.”

The approval “marks an important advance, and provides a reason for optimism for the many patients who will receive pain relief” with pregabalin, Dr. Steven Galson, the director of the FDA's Center for Drug Evaluation and Research said in the FDA statement. He added, however, that consumers should understand that some patients in trials did not benefit from the drug, and that “we still have more progress to make for treatment of this disorder.”

The two studies enrolled patients diagnosed with fibromyalgia using American College of Rheumatology (ACR) criteria, which are a history of widespread pain for 3 months and pain present at 11 or more of the 18 specific tender point sites, according to the revised prescribing information for pregabalin. The two studies–a 14-week double-blind placebo-controlled study and a 6-month randomized withdrawal study–found that treatment was associated with a reduction in pain by visual analog scale and improvements based on a patient global assessment and on the Fibromyalgia Impact Questionnaire.

In the 14-week study, some patients experienced reductions in pain during the first week of treatment, which continued throughout the study. Nearly 70% of those on a total daily dose of 300 mg of pregabalin, and 78% of those on a total daily dose of 450 mg experienced any improvement on the patient global impression of change scale, compared with 48% of those on placebo. The total daily dose of 600 mg was not more effective than the lower doses, and there was evidence of dose-related side effects.

The daily dose should be administered in two divided doses per day, starting at a total daily dose of 150 mg/day, which may be increased to 300 mg/day, within 1 week; the maximum dose is 450 mg/day, according to the prescribing information.

The most common side effects in the trials were mild to moderate dizziness and sleepiness, blurred vision, weight gain, dry mouth, and swelling of the hands and feet also were also reported. Side effects appeared to be dose related, according to the FDA. Patients should talk to their physicians or other health care providers about whether pregabalin–which can impair motor function, concentration, and attention–can affect their ability to drive, the FDA advised. Pfizer has agreed to conduct a study of pregabalin in children and another in women who are breast-feeding.

Pregabalin, a centrally acting drug, was first approved in 2004 for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia, and for the adjunctive therapy for adult patients with partial onset seizures. It is taken orally in capsule form.

Pregabalin has become the first drug to win approval by the Food and Drug Administration for the management of fibromyalgia.

The FDA based the approval on two double-blind, controlled trials of approximately 1,800 patients. Data from the studies have shown that patients with fibromyalgia “have decreased pain after taking [pregabalin], but, the mechanism by which [pregabalin] produces such an effect is unknown,” according to an agency-issued statement.

In the clinical trials of patients with fibromyalgia, those on pregabalin (Lyrica) had “rapid and sustained improvements in pain,” compared with those on placebo, and “reported feeling better and improvements in physical function,” according to a statement issued by Pfizer, which manufactures pregabalin. The same statement explains that the drug's mechanism of action for fibromyalgia is not known, but states that patients with fibromyalgia may be more sensitive than normal to stimuli that are not usually painful, and that pregabalin may reduce the degree of pain experienced by patients with fibromyalgia by binding to a specific protein within “overexcited nerve cells.”

The approval “marks an important advance, and provides a reason for optimism for the many patients who will receive pain relief” with pregabalin, Dr. Steven Galson, the director of the FDA's Center for Drug Evaluation and Research said in the FDA statement. He added, however, that consumers should understand that some patients in trials did not benefit from the drug, and that “we still have more progress to make for treatment of this disorder.”

The two studies enrolled patients diagnosed with fibromyalgia using American College of Rheumatology (ACR) criteria, which are a history of widespread pain for 3 months and pain present at 11 or more of the 18 specific tender point sites, according to the revised prescribing information for pregabalin. The two studies–a 14-week double-blind placebo-controlled study and a 6-month randomized withdrawal study–found that treatment was associated with a reduction in pain by visual analog scale and improvements based on a patient global assessment and on the Fibromyalgia Impact Questionnaire.

In the 14-week study, some patients experienced reductions in pain during the first week of treatment, which continued throughout the study. Nearly 70% of those on a total daily dose of 300 mg of pregabalin, and 78% of those on a total daily dose of 450 mg experienced any improvement on the patient global impression of change scale, compared with 48% of those on placebo. The total daily dose of 600 mg was not more effective than the lower doses, and there was evidence of dose-related side effects.

The daily dose should be administered in two divided doses per day, starting at a total daily dose of 150 mg/day, which may be increased to 300 mg/day, within 1 week; the maximum dose is 450 mg/day, according to the prescribing information.

The most common side effects in the trials were mild to moderate dizziness and sleepiness, blurred vision, weight gain, dry mouth, and swelling of the hands and feet also were also reported. Side effects appeared to be dose related, according to the FDA. Patients should talk to their physicians or other health care providers about whether pregabalin–which can impair motor function, concentration, and attention–can affect their ability to drive, the FDA advised. Pfizer has agreed to conduct a study of pregabalin in children and another in women who are breast-feeding.

Pregabalin, a centrally acting drug, was first approved in 2004 for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia, and for the adjunctive therapy for adult patients with partial onset seizures. It is taken orally in capsule form.

GAITHERSBURG, MD. — The majority of a federal advisory panel recommended that a cryoablation system be approved for treating atrial flutter in adults, under certain conditions that include a postmarketing study of treatment recipients conducted by the manufacturer to further evaluate its safety and efficacy.

If approved, the device, the CryoCor Cryoablation System, would be the first cryoablation device approved in the United States for treating atrial flutter.

At a recent meeting, the Food and Drug Administration's circulatory system devices panel voted 8–2 that the device was “approvable with conditions,” for treating isthmus-dependent atrial flutter in patients aged 18 years and older. Two conditions for approval pertained to labeling issues for the device and requirements for training of physicians and their staffs in how to use the console and manipulate the catheter. The third condition was that the manufacturer, San Diego-based CryoCor Inc., conduct a postmarketing registry study of patients treated with the device, to follow the short-term and longer-term adverse events and clinical effectiveness in a real-world setting.

Despite reservations about the design and results of the clinical trial submitted for approval, the majority of the panel agreed that the data presented by the company had shown that there was “reasonable assurance” that the device was safe and effective for treating right isthmus-dependent atrial flutter. The main issue was that the clinical trial did not compare the device with a control group, but instead compared it with established safety and efficacy objective performance criteria (OPC) for current standard ablation treatment modalities, agreed upon by the FDA and company.

Dr. David Slotwiner, an electrophysiologist at Long Island Jewish Medical Center, New Hyde Park, N.Y., said that he believed that the data demonstrated that the device was safe and effective for treating the proposed indication. But like others on the panel, he strongly agreed that it was not appropriate to use the OPC for such studies and that in the future, these devices be studied in randomized, controlled trials that include a comparator group of patients.

The FDA usually follows the advice of its advisory panels, which are not binding. The FDA decision is expected in August, according to CryoCor, which is now conducting a study of the system for treating atrial fibrillation.

The system includes a console and a percutaneous catheter, which ablates cardiac tissue by freezing it, using nitrous oxide. In the pivotal study conducted at 24 U.S. sites, 160 patients, with documented, symptomatic isthmus-dependent atrial flutter and with at least one episode within the previous 6 months, were treated with the system. (Exclusion criteria included structural heart disease, unstable heart failure symptoms, and having undergone ablation for atrial flutter previously.)

Acute effectiveness, defined as the proportion of patients achieving bidirectional block across the cavotricuspid isthmus, was 87.5% (140 of 160 patients), which met the goal of more than 80% acute effectiveness rate. The primary safety end point, serious adverse events within 7 days of the procedure, was not met; however, the rate was 5.6%, more than twice as high as the prespecified goal of 2.5%. Dr. Randall Brockman, the FDA's primary reviewer of the application, said that although the primary safety end point was not met, the agency believed that the events that occurred were similar to those that would be expected for patients with atrial flutter.

Chronic effectiveness, based on evaluations by the blinded core lab adjudication of patient event recordings, was 81.6%, which did not meet the prespecified chronic effectiveness goal of 90%.

One of the two panelists voting against approval, cardiac surgeon Norman S. Kato, said there was insufficient evidence to satisfy the objective performance criteria. He also pointed out that atrial flutter usually is not a life-threatening problem, and that a 2- to 2.5-fold higher complication rate “in a situation where the disease is not life threatening is a problem.”

Also voting against approval was the panel's statistician, Sharon-Lise Normand, Ph.D., of Harvard School of Public Health, Boston, who said that the data did not support approval and also remarked that she was concerned that “subjective opinions” were behind many of the votes for approval.

GAITHERSBURG, MD. — The majority of a federal advisory panel recommended that a cryoablation system be approved for treating atrial flutter in adults, under certain conditions that include a postmarketing study of treatment recipients conducted by the manufacturer to further evaluate its safety and efficacy.

If approved, the device, the CryoCor Cryoablation System, would be the first cryoablation device approved in the United States for treating atrial flutter.

At a recent meeting, the Food and Drug Administration's circulatory system devices panel voted 8–2 that the device was “approvable with conditions,” for treating isthmus-dependent atrial flutter in patients aged 18 years and older. Two conditions for approval pertained to labeling issues for the device and requirements for training of physicians and their staffs in how to use the console and manipulate the catheter. The third condition was that the manufacturer, San Diego-based CryoCor Inc., conduct a postmarketing registry study of patients treated with the device, to follow the short-term and longer-term adverse events and clinical effectiveness in a real-world setting.

Despite reservations about the design and results of the clinical trial submitted for approval, the majority of the panel agreed that the data presented by the company had shown that there was “reasonable assurance” that the device was safe and effective for treating right isthmus-dependent atrial flutter. The main issue was that the clinical trial did not compare the device with a control group, but instead compared it with established safety and efficacy objective performance criteria (OPC) for current standard ablation treatment modalities, agreed upon by the FDA and company.

Dr. David Slotwiner, an electrophysiologist at Long Island Jewish Medical Center, New Hyde Park, N.Y., said that he believed that the data demonstrated that the device was safe and effective for treating the proposed indication. But like others on the panel, he strongly agreed that it was not appropriate to use the OPC for such studies and that in the future, these devices be studied in randomized, controlled trials that include a comparator group of patients.

The FDA usually follows the advice of its advisory panels, which are not binding. The FDA decision is expected in August, according to CryoCor, which is now conducting a study of the system for treating atrial fibrillation.

The system includes a console and a percutaneous catheter, which ablates cardiac tissue by freezing it, using nitrous oxide. In the pivotal study conducted at 24 U.S. sites, 160 patients, with documented, symptomatic isthmus-dependent atrial flutter and with at least one episode within the previous 6 months, were treated with the system. (Exclusion criteria included structural heart disease, unstable heart failure symptoms, and having undergone ablation for atrial flutter previously.)

Acute effectiveness, defined as the proportion of patients achieving bidirectional block across the cavotricuspid isthmus, was 87.5% (140 of 160 patients), which met the goal of more than 80% acute effectiveness rate. The primary safety end point, serious adverse events within 7 days of the procedure, was not met; however, the rate was 5.6%, more than twice as high as the prespecified goal of 2.5%. Dr. Randall Brockman, the FDA's primary reviewer of the application, said that although the primary safety end point was not met, the agency believed that the events that occurred were similar to those that would be expected for patients with atrial flutter.

Chronic effectiveness, based on evaluations by the blinded core lab adjudication of patient event recordings, was 81.6%, which did not meet the prespecified chronic effectiveness goal of 90%.

One of the two panelists voting against approval, cardiac surgeon Norman S. Kato, said there was insufficient evidence to satisfy the objective performance criteria. He also pointed out that atrial flutter usually is not a life-threatening problem, and that a 2- to 2.5-fold higher complication rate “in a situation where the disease is not life threatening is a problem.”

Also voting against approval was the panel's statistician, Sharon-Lise Normand, Ph.D., of Harvard School of Public Health, Boston, who said that the data did not support approval and also remarked that she was concerned that “subjective opinions” were behind many of the votes for approval.

GAITHERSBURG, MD. — The majority of a federal advisory panel recommended that a cryoablation system be approved for treating atrial flutter in adults, under certain conditions that include a postmarketing study of treatment recipients conducted by the manufacturer to further evaluate its safety and efficacy.

If approved, the device, the CryoCor Cryoablation System, would be the first cryoablation device approved in the United States for treating atrial flutter.

At a recent meeting, the Food and Drug Administration's circulatory system devices panel voted 8–2 that the device was “approvable with conditions,” for treating isthmus-dependent atrial flutter in patients aged 18 years and older. Two conditions for approval pertained to labeling issues for the device and requirements for training of physicians and their staffs in how to use the console and manipulate the catheter. The third condition was that the manufacturer, San Diego-based CryoCor Inc., conduct a postmarketing registry study of patients treated with the device, to follow the short-term and longer-term adverse events and clinical effectiveness in a real-world setting.

Despite reservations about the design and results of the clinical trial submitted for approval, the majority of the panel agreed that the data presented by the company had shown that there was “reasonable assurance” that the device was safe and effective for treating right isthmus-dependent atrial flutter. The main issue was that the clinical trial did not compare the device with a control group, but instead compared it with established safety and efficacy objective performance criteria (OPC) for current standard ablation treatment modalities, agreed upon by the FDA and company.

Dr. David Slotwiner, an electrophysiologist at Long Island Jewish Medical Center, New Hyde Park, N.Y., said that he believed that the data demonstrated that the device was safe and effective for treating the proposed indication. But like others on the panel, he strongly agreed that it was not appropriate to use the OPC for such studies and that in the future, these devices be studied in randomized, controlled trials that include a comparator group of patients.

The FDA usually follows the advice of its advisory panels, which are not binding. The FDA decision is expected in August, according to CryoCor, which is now conducting a study of the system for treating atrial fibrillation.

The system includes a console and a percutaneous catheter, which ablates cardiac tissue by freezing it, using nitrous oxide. In the pivotal study conducted at 24 U.S. sites, 160 patients, with documented, symptomatic isthmus-dependent atrial flutter and with at least one episode within the previous 6 months, were treated with the system. (Exclusion criteria included structural heart disease, unstable heart failure symptoms, and having undergone ablation for atrial flutter previously.)

Acute effectiveness, defined as the proportion of patients achieving bidirectional block across the cavotricuspid isthmus, was 87.5% (140 of 160 patients), which met the goal of more than 80% acute effectiveness rate. The primary safety end point, serious adverse events within 7 days of the procedure, was not met; however, the rate was 5.6%, more than twice as high as the prespecified goal of 2.5%. Dr. Randall Brockman, the FDA's primary reviewer of the application, said that although the primary safety end point was not met, the agency believed that the events that occurred were similar to those that would be expected for patients with atrial flutter.

Chronic effectiveness, based on evaluations by the blinded core lab adjudication of patient event recordings, was 81.6%, which did not meet the prespecified chronic effectiveness goal of 90%.

One of the two panelists voting against approval, cardiac surgeon Norman S. Kato, said there was insufficient evidence to satisfy the objective performance criteria. He also pointed out that atrial flutter usually is not a life-threatening problem, and that a 2- to 2.5-fold higher complication rate “in a situation where the disease is not life threatening is a problem.”

Also voting against approval was the panel's statistician, Sharon-Lise Normand, Ph.D., of Harvard School of Public Health, Boston, who said that the data did not support approval and also remarked that she was concerned that “subjective opinions” were behind many of the votes for approval.

As of mid-June, stocks of ProQuad were depleted because of manufacturing issues, and the combination vaccine was not expected to be available for the rest of the year, according to the Centers for Disease Control and Prevention. ProQuad is the combined attenuated live virus vaccine that contains measles, mumps, rubella, and varicella viruses—the components of the M-M-R II and varicella (Varivax) vaccines. Because of lower-than-expected yields of varicella-zoster virus (VZV), which is used to manufacture the Varivax, zoster (Zostavax), and ProQuad vaccines, their manufacturer, Merck & Co., had prioritized the production of Varivax and Zostavax over that of ProQuad. Then production of VZV bulk was temporarily suspended because of low yields.

The reduced supply of ProQuad was first announced in the CDC's Morbidity and Mortality Weekly Report (2007;56:453), which said that Merck had notified the CDC in February about the problem, and notified the CDC in May that projections of ProQuad orders indicated that the vaccine would no longer be available as of July, “although timing will depend on market demand.” Physicians can use M-M-R II and Varivax instead of ProQuad, according to the CDC notice.

It is expected that there will be an adequate supply of these vaccines to fully implement the recommended immunization schedule for varicella vaccine for all age groups and for the recommended use of zoster vaccine. For Varivax, this includes the routine two-dose schedule for children aged 12–15 months and 4–6 years; catch-up vaccination with the second dose for children and adolescents who received only one dose; and vaccination with two doses for other children, adolescents, and adults with no evidence of immunity.

As of mid-June, stocks of ProQuad were depleted because of manufacturing issues, and the combination vaccine was not expected to be available for the rest of the year, according to the Centers for Disease Control and Prevention. ProQuad is the combined attenuated live virus vaccine that contains measles, mumps, rubella, and varicella viruses—the components of the M-M-R II and varicella (Varivax) vaccines. Because of lower-than-expected yields of varicella-zoster virus (VZV), which is used to manufacture the Varivax, zoster (Zostavax), and ProQuad vaccines, their manufacturer, Merck & Co., had prioritized the production of Varivax and Zostavax over that of ProQuad. Then production of VZV bulk was temporarily suspended because of low yields.

The reduced supply of ProQuad was first announced in the CDC's Morbidity and Mortality Weekly Report (2007;56:453), which said that Merck had notified the CDC in February about the problem, and notified the CDC in May that projections of ProQuad orders indicated that the vaccine would no longer be available as of July, “although timing will depend on market demand.” Physicians can use M-M-R II and Varivax instead of ProQuad, according to the CDC notice.

It is expected that there will be an adequate supply of these vaccines to fully implement the recommended immunization schedule for varicella vaccine for all age groups and for the recommended use of zoster vaccine. For Varivax, this includes the routine two-dose schedule for children aged 12–15 months and 4–6 years; catch-up vaccination with the second dose for children and adolescents who received only one dose; and vaccination with two doses for other children, adolescents, and adults with no evidence of immunity.

As of mid-June, stocks of ProQuad were depleted because of manufacturing issues, and the combination vaccine was not expected to be available for the rest of the year, according to the Centers for Disease Control and Prevention. ProQuad is the combined attenuated live virus vaccine that contains measles, mumps, rubella, and varicella viruses—the components of the M-M-R II and varicella (Varivax) vaccines. Because of lower-than-expected yields of varicella-zoster virus (VZV), which is used to manufacture the Varivax, zoster (Zostavax), and ProQuad vaccines, their manufacturer, Merck & Co., had prioritized the production of Varivax and Zostavax over that of ProQuad. Then production of VZV bulk was temporarily suspended because of low yields.

The reduced supply of ProQuad was first announced in the CDC's Morbidity and Mortality Weekly Report (2007;56:453), which said that Merck had notified the CDC in February about the problem, and notified the CDC in May that projections of ProQuad orders indicated that the vaccine would no longer be available as of July, “although timing will depend on market demand.” Physicians can use M-M-R II and Varivax instead of ProQuad, according to the CDC notice.

It is expected that there will be an adequate supply of these vaccines to fully implement the recommended immunization schedule for varicella vaccine for all age groups and for the recommended use of zoster vaccine. For Varivax, this includes the routine two-dose schedule for children aged 12–15 months and 4–6 years; catch-up vaccination with the second dose for children and adolescents who received only one dose; and vaccination with two doses for other children, adolescents, and adults with no evidence of immunity.

A 5-mg intravenous formulation of zoledronic acid has been approved by the Food and Drug Administration for treating Paget's disease of bone, based on 6-month studies that found that a single infusion resulted in superior and more sustained responses than did 60 days of daily treatment with an oral bisphosphonate.

The package insert says that treatment is indicated “to induce remission” in patients with elevations in serum alkaline phosphatase (ALP) that are at least two times the upper limit of the age-specific normal reference range, or in patients who are symptomatic or are at risk for complications from the disease. Remission is defined as normalization of serum ALP.

The 5-mg formulation of the potent bisphosphonate, marketed as Reclast by Novartis Pharmaceuticals Corp., is administered as a single intravenous infusion over 15 minutes. Reclast, which is under review at the FDA for approval as a treatment for postmenopausal osteoporosis, is approved for Paget's disease in more than 50 countries, according to Novartis.

In the two 6-month identical studies, published in 2005, of 347 men and women with moderate to severe radiographically confirmed Paget's disease—all of whom had serum ALP levels as stated in the indication—the patients received either a single infusion of Reclast at the start of the study or daily doses of 30 mg of risedronate (Actonel) for 60 days. At 6 months, 96% of those who received Reclast had had a therapeutic response (defined as normalization of the ALP level or a reduction of at least three-fourths of ALP excess), compared with 74% of those on risedronate.

Levels dropped significantly more rapidly among those on Reclast, and ALP levels normalized in nearly 90% of those on Reclast, versus 58% of those on risedronate, also highly significant. The higher response rates associated with Reclast were independent of age, sex, baseline ALP, and the presence or absence of previous therapies for Paget's.

Pain scores improved in both groups, and there were trends toward improved quality of life at 3 and 6 months, as measured with a patient questionnaire, among those on Reclast, with more mixed results among those on risedronate. During a mean 190-day extension of the study in patients who had had a therapeutic response, the therapeutic response was lost in nearly 26% of those on risedronate vs. 0.9% of those on Reclast.

Those who received the infusion had twice as many adverse events in the first 3 days of treatment, primarily influenzalike symptoms that were mild to moderate; most resolved after 4 days. The rates of GI and renal or urinary disorders were similar; one patient in each group had moderate increases in serum creatinine levels, and eight patients on Reclast and one patient on risedronate developed hypocalcemia (N. Engl. J. Med. 2005;353:898–908).

“There is quite a long biochemical and clinical remission when this drug is used,” said Dr. Kenneth W. Lyles, professor of medicine at Duke University, Durham, N.C., who was one of the studies' authors. He disclosed that he has received research support from and serves as a consultant to Novartis.

Reclast is contraindicated in hypocalcemia and during pregnancy and lactation, and is not recommended for patients with severe renal impairment, according to the label.

A 5-mg intravenous formulation of zoledronic acid has been approved by the Food and Drug Administration for treating Paget's disease of bone, based on 6-month studies that found that a single infusion resulted in superior and more sustained responses than did 60 days of daily treatment with an oral bisphosphonate.

The package insert says that treatment is indicated “to induce remission” in patients with elevations in serum alkaline phosphatase (ALP) that are at least two times the upper limit of the age-specific normal reference range, or in patients who are symptomatic or are at risk for complications from the disease. Remission is defined as normalization of serum ALP.

The 5-mg formulation of the potent bisphosphonate, marketed as Reclast by Novartis Pharmaceuticals Corp., is administered as a single intravenous infusion over 15 minutes. Reclast, which is under review at the FDA for approval as a treatment for postmenopausal osteoporosis, is approved for Paget's disease in more than 50 countries, according to Novartis.

In the two 6-month identical studies, published in 2005, of 347 men and women with moderate to severe radiographically confirmed Paget's disease—all of whom had serum ALP levels as stated in the indication—the patients received either a single infusion of Reclast at the start of the study or daily doses of 30 mg of risedronate (Actonel) for 60 days. At 6 months, 96% of those who received Reclast had had a therapeutic response (defined as normalization of the ALP level or a reduction of at least three-fourths of ALP excess), compared with 74% of those on risedronate.

Levels dropped significantly more rapidly among those on Reclast, and ALP levels normalized in nearly 90% of those on Reclast, versus 58% of those on risedronate, also highly significant. The higher response rates associated with Reclast were independent of age, sex, baseline ALP, and the presence or absence of previous therapies for Paget's.

Pain scores improved in both groups, and there were trends toward improved quality of life at 3 and 6 months, as measured with a patient questionnaire, among those on Reclast, with more mixed results among those on risedronate. During a mean 190-day extension of the study in patients who had had a therapeutic response, the therapeutic response was lost in nearly 26% of those on risedronate vs. 0.9% of those on Reclast.

Those who received the infusion had twice as many adverse events in the first 3 days of treatment, primarily influenzalike symptoms that were mild to moderate; most resolved after 4 days. The rates of GI and renal or urinary disorders were similar; one patient in each group had moderate increases in serum creatinine levels, and eight patients on Reclast and one patient on risedronate developed hypocalcemia (N. Engl. J. Med. 2005;353:898–908).

“There is quite a long biochemical and clinical remission when this drug is used,” said Dr. Kenneth W. Lyles, professor of medicine at Duke University, Durham, N.C., who was one of the studies' authors. He disclosed that he has received research support from and serves as a consultant to Novartis.

Reclast is contraindicated in hypocalcemia and during pregnancy and lactation, and is not recommended for patients with severe renal impairment, according to the label.

A 5-mg intravenous formulation of zoledronic acid has been approved by the Food and Drug Administration for treating Paget's disease of bone, based on 6-month studies that found that a single infusion resulted in superior and more sustained responses than did 60 days of daily treatment with an oral bisphosphonate.

The package insert says that treatment is indicated “to induce remission” in patients with elevations in serum alkaline phosphatase (ALP) that are at least two times the upper limit of the age-specific normal reference range, or in patients who are symptomatic or are at risk for complications from the disease. Remission is defined as normalization of serum ALP.

The 5-mg formulation of the potent bisphosphonate, marketed as Reclast by Novartis Pharmaceuticals Corp., is administered as a single intravenous infusion over 15 minutes. Reclast, which is under review at the FDA for approval as a treatment for postmenopausal osteoporosis, is approved for Paget's disease in more than 50 countries, according to Novartis.

In the two 6-month identical studies, published in 2005, of 347 men and women with moderate to severe radiographically confirmed Paget's disease—all of whom had serum ALP levels as stated in the indication—the patients received either a single infusion of Reclast at the start of the study or daily doses of 30 mg of risedronate (Actonel) for 60 days. At 6 months, 96% of those who received Reclast had had a therapeutic response (defined as normalization of the ALP level or a reduction of at least three-fourths of ALP excess), compared with 74% of those on risedronate.

Levels dropped significantly more rapidly among those on Reclast, and ALP levels normalized in nearly 90% of those on Reclast, versus 58% of those on risedronate, also highly significant. The higher response rates associated with Reclast were independent of age, sex, baseline ALP, and the presence or absence of previous therapies for Paget's.

Pain scores improved in both groups, and there were trends toward improved quality of life at 3 and 6 months, as measured with a patient questionnaire, among those on Reclast, with more mixed results among those on risedronate. During a mean 190-day extension of the study in patients who had had a therapeutic response, the therapeutic response was lost in nearly 26% of those on risedronate vs. 0.9% of those on Reclast.

Those who received the infusion had twice as many adverse events in the first 3 days of treatment, primarily influenzalike symptoms that were mild to moderate; most resolved after 4 days. The rates of GI and renal or urinary disorders were similar; one patient in each group had moderate increases in serum creatinine levels, and eight patients on Reclast and one patient on risedronate developed hypocalcemia (N. Engl. J. Med. 2005;353:898–908).

“There is quite a long biochemical and clinical remission when this drug is used,” said Dr. Kenneth W. Lyles, professor of medicine at Duke University, Durham, N.C., who was one of the studies' authors. He disclosed that he has received research support from and serves as a consultant to Novartis.

Reclast is contraindicated in hypocalcemia and during pregnancy and lactation, and is not recommended for patients with severe renal impairment, according to the label.

At least one shortcoming of currently available therapy for pulmonary arterial hypertension may become irrelevant with the Food and Drug Administration approval of the endothelin receptor antagonist ambrisentan last month.

In a statement issued by the FDA announcing the approval, Dr. John Jenkins, director of the FDA's Office of New Drugs, said that ambrisentan “is similar to an existing drug, but offers the potential for fewer drug interactions.”

The FDA based its approval on findings from two studies of almost 400 patients that found treatment significantly increased physical activity capacity and delayed progression of the disease.

This is the sixth drug approved by the FDA for treating PAH; the others are epoprostenol, treprostinil, iloprost, bosentan, and sildenafil, which have all been approved over the last decade. Another endothelin receptor antagonist, sitaxsentan, is approved in Europe, Canada, and Australia, and has been under FDA review.

Over the last decade, the treatment options for PAH have expanded from a treatment that is administered in an intravenous infusion—epoprostenol—to treatments that include oral and inhaled medications, with wide use of combination therapy, because not all patients respond to monotherapy, said Dr. Lewis J. Rubin, professor of medicine at the University of California, San Diego.

The approved indication for ambrisentan is for treatment of PAH (WHO Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening. Ambrisentan is being marketed under the trade name Letairis by Gilead Sciences Inc., which acquired Myogen Inc., the developer of the drug, in 2006.

The recommended dosage regimen is to start at 5 mg once a day, and if tolerated, to consider increasing the dosage to 10 mg once a day. Because it is teratogenic and has a potential risk of liver toxicity, the drug is available only through a restricted distribution program, the Letairis Education and Access Program (LEAP). Health care professionals, pharmacists, and patients must enroll in this program before they can prescribe, dispense, or receive the drug.

In an interview, Dr. Rubin said bosentan (Tracleer), the endothelin receptor antagonist approved for PAH in 2001, can interact with sildenafil, increasing the metabolism of sildenafil and reducing the metabolism of bosentan. (Sildenafil, marketed as Viagra for erectile dysfunction, is marketed as Revatio for PAH.) The two can be taken together, but optimal dosing is “challenging,” he said.

Ambrisentan is taken once a day, compared with twice a day for bosentan, and the incidence of liver function abnormalities—the major potential toxicity of the endothelin receptor antagonist class—appears to be lower with ambrisentan based on available data, Dr. Rubin said. He added, however, that bosentan has been available longer, so there are more long-term data on the drug. Both appear to be equally efficacious, he said.

Dr. Rubin was the principal investigator of the ARIES-1 and ARIES-2 trials, which “demonstrated that ambrisentan is effective in a number of parameters of disease severity in patients with pulmonary hypertension and that it is a safe drug,” he said. He also served as a consultant to Gilead in the development of the drug.

In the 12-week studies, 393 people with PAH received either placebo or ambrisentan added to current treatment (which could not include any of the drugs approved for PAH).

Compared with placebo, those on ambrisentan had significant improvements in the primary end point, the 6-minute walk distance, at 12 weeks. There was also a significant delay among those on ambrisentan in the time to clinical worsening of PAH.

The most common side effects associated with the drug were peripheral edema, a known class effect of endothelin receptor antagonists, which was usually mild to moderate; nasal congestion; sinusitis; and flushing, according to the FDA. The rate of treatment discontinuations because of side effects was similar (about 2%) for those on placebo and the drug.

Monthly liver function testing is necessary during treatment with ambrisentan. This is a pregnancy category X drug.

At least one shortcoming of currently available therapy for pulmonary arterial hypertension may become irrelevant with the Food and Drug Administration approval of the endothelin receptor antagonist ambrisentan last month.

In a statement issued by the FDA announcing the approval, Dr. John Jenkins, director of the FDA's Office of New Drugs, said that ambrisentan “is similar to an existing drug, but offers the potential for fewer drug interactions.”

The FDA based its approval on findings from two studies of almost 400 patients that found treatment significantly increased physical activity capacity and delayed progression of the disease.

This is the sixth drug approved by the FDA for treating PAH; the others are epoprostenol, treprostinil, iloprost, bosentan, and sildenafil, which have all been approved over the last decade. Another endothelin receptor antagonist, sitaxsentan, is approved in Europe, Canada, and Australia, and has been under FDA review.

Over the last decade, the treatment options for PAH have expanded from a treatment that is administered in an intravenous infusion—epoprostenol—to treatments that include oral and inhaled medications, with wide use of combination therapy, because not all patients respond to monotherapy, said Dr. Lewis J. Rubin, professor of medicine at the University of California, San Diego.

The approved indication for ambrisentan is for treatment of PAH (WHO Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening. Ambrisentan is being marketed under the trade name Letairis by Gilead Sciences Inc., which acquired Myogen Inc., the developer of the drug, in 2006.

The recommended dosage regimen is to start at 5 mg once a day, and if tolerated, to consider increasing the dosage to 10 mg once a day. Because it is teratogenic and has a potential risk of liver toxicity, the drug is available only through a restricted distribution program, the Letairis Education and Access Program (LEAP). Health care professionals, pharmacists, and patients must enroll in this program before they can prescribe, dispense, or receive the drug.

In an interview, Dr. Rubin said bosentan (Tracleer), the endothelin receptor antagonist approved for PAH in 2001, can interact with sildenafil, increasing the metabolism of sildenafil and reducing the metabolism of bosentan. (Sildenafil, marketed as Viagra for erectile dysfunction, is marketed as Revatio for PAH.) The two can be taken together, but optimal dosing is “challenging,” he said.

Ambrisentan is taken once a day, compared with twice a day for bosentan, and the incidence of liver function abnormalities—the major potential toxicity of the endothelin receptor antagonist class—appears to be lower with ambrisentan based on available data, Dr. Rubin said. He added, however, that bosentan has been available longer, so there are more long-term data on the drug. Both appear to be equally efficacious, he said.

Dr. Rubin was the principal investigator of the ARIES-1 and ARIES-2 trials, which “demonstrated that ambrisentan is effective in a number of parameters of disease severity in patients with pulmonary hypertension and that it is a safe drug,” he said. He also served as a consultant to Gilead in the development of the drug.

In the 12-week studies, 393 people with PAH received either placebo or ambrisentan added to current treatment (which could not include any of the drugs approved for PAH).

Compared with placebo, those on ambrisentan had significant improvements in the primary end point, the 6-minute walk distance, at 12 weeks. There was also a significant delay among those on ambrisentan in the time to clinical worsening of PAH.

The most common side effects associated with the drug were peripheral edema, a known class effect of endothelin receptor antagonists, which was usually mild to moderate; nasal congestion; sinusitis; and flushing, according to the FDA. The rate of treatment discontinuations because of side effects was similar (about 2%) for those on placebo and the drug.

Monthly liver function testing is necessary during treatment with ambrisentan. This is a pregnancy category X drug.

At least one shortcoming of currently available therapy for pulmonary arterial hypertension may become irrelevant with the Food and Drug Administration approval of the endothelin receptor antagonist ambrisentan last month.

In a statement issued by the FDA announcing the approval, Dr. John Jenkins, director of the FDA's Office of New Drugs, said that ambrisentan “is similar to an existing drug, but offers the potential for fewer drug interactions.”

The FDA based its approval on findings from two studies of almost 400 patients that found treatment significantly increased physical activity capacity and delayed progression of the disease.

This is the sixth drug approved by the FDA for treating PAH; the others are epoprostenol, treprostinil, iloprost, bosentan, and sildenafil, which have all been approved over the last decade. Another endothelin receptor antagonist, sitaxsentan, is approved in Europe, Canada, and Australia, and has been under FDA review.

Over the last decade, the treatment options for PAH have expanded from a treatment that is administered in an intravenous infusion—epoprostenol—to treatments that include oral and inhaled medications, with wide use of combination therapy, because not all patients respond to monotherapy, said Dr. Lewis J. Rubin, professor of medicine at the University of California, San Diego.

The approved indication for ambrisentan is for treatment of PAH (WHO Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening. Ambrisentan is being marketed under the trade name Letairis by Gilead Sciences Inc., which acquired Myogen Inc., the developer of the drug, in 2006.

The recommended dosage regimen is to start at 5 mg once a day, and if tolerated, to consider increasing the dosage to 10 mg once a day. Because it is teratogenic and has a potential risk of liver toxicity, the drug is available only through a restricted distribution program, the Letairis Education and Access Program (LEAP). Health care professionals, pharmacists, and patients must enroll in this program before they can prescribe, dispense, or receive the drug.

In an interview, Dr. Rubin said bosentan (Tracleer), the endothelin receptor antagonist approved for PAH in 2001, can interact with sildenafil, increasing the metabolism of sildenafil and reducing the metabolism of bosentan. (Sildenafil, marketed as Viagra for erectile dysfunction, is marketed as Revatio for PAH.) The two can be taken together, but optimal dosing is “challenging,” he said.

Ambrisentan is taken once a day, compared with twice a day for bosentan, and the incidence of liver function abnormalities—the major potential toxicity of the endothelin receptor antagonist class—appears to be lower with ambrisentan based on available data, Dr. Rubin said. He added, however, that bosentan has been available longer, so there are more long-term data on the drug. Both appear to be equally efficacious, he said.

Dr. Rubin was the principal investigator of the ARIES-1 and ARIES-2 trials, which “demonstrated that ambrisentan is effective in a number of parameters of disease severity in patients with pulmonary hypertension and that it is a safe drug,” he said. He also served as a consultant to Gilead in the development of the drug.

In the 12-week studies, 393 people with PAH received either placebo or ambrisentan added to current treatment (which could not include any of the drugs approved for PAH).

Compared with placebo, those on ambrisentan had significant improvements in the primary end point, the 6-minute walk distance, at 12 weeks. There was also a significant delay among those on ambrisentan in the time to clinical worsening of PAH.

The most common side effects associated with the drug were peripheral edema, a known class effect of endothelin receptor antagonists, which was usually mild to moderate; nasal congestion; sinusitis; and flushing, according to the FDA. The rate of treatment discontinuations because of side effects was similar (about 2%) for those on placebo and the drug.

Monthly liver function testing is necessary during treatment with ambrisentan. This is a pregnancy category X drug.

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 of the study concluded (Pediatr. Infect. Dis. J. 2007;26:496–500). They pointed out that while 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 Jan. 1 through Sept. 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 (the lead author) and some of the other researchers are from the University of Louisville, Ky; other investigators were from the Georgia Medicaid program and Xcenda, listed in the study's acknowledgments section as a research service company contracted by Pediarix manufacturer GlaxoSmithKline (GSK) to help conduct the study. The acknowledgments 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. In addition, Dr. Charles Woods, another author also at the university, has been an investigator on clinical trials funded by Sanofi Pasteur and Merck, and has received honoraria for lectures and service on their advisory boards.

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 of the study concluded (Pediatr. Infect. Dis. J. 2007;26:496–500). They pointed out that while 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 Jan. 1 through Sept. 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 (the lead author) and some of the other researchers are from the University of Louisville, Ky; other investigators were from the Georgia Medicaid program and Xcenda, listed in the study's acknowledgments section as a research service company contracted by Pediarix manufacturer GlaxoSmithKline (GSK) to help conduct the study. The acknowledgments 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. In addition, Dr. Charles Woods, another author also at the university, has been an investigator on clinical trials funded by Sanofi Pasteur and Merck, and has received honoraria for lectures and service on their advisory boards.

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 of the study concluded (Pediatr. Infect. Dis. J. 2007;26:496–500). They pointed out that while 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 Jan. 1 through Sept. 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 (the lead author) and some of the other researchers are from the University of Louisville, Ky; other investigators were from the Georgia Medicaid program and Xcenda, listed in the study's acknowledgments section as a research service company contracted by Pediarix manufacturer GlaxoSmithKline (GSK) to help conduct the study. The acknowledgments 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. In addition, Dr. Charles Woods, another author also at the university, has been an investigator on clinical trials funded by Sanofi Pasteur and Merck, and has received honoraria for lectures and service on their advisory boards.

Several postmarketing reports of Kawasaki disease in recipients of the RotaTeq vaccine have prompted changes in the vaccine's label, but to date there is no known cause-and-effect relationship between the vaccine and these reports, according to the Food and Drug Administration.

Last month, the FDA approved the labeling changes, which add information to the adverse reactions and postmarketing sections of the vaccine's label. The information added includes six cases of Kawasaki disease that were observed in the phase III clinical trial of RotaTeq—five cases among 36,150 infants who received RotaTeq and one case among 35,536 infants who received the placebo.

There have been three additional cases of Kawasaki disease reported to the Vaccine Adverse Event Reporting System (VAERS) since RotaTeq was approved in February 2006 for preventing rotavirus infection—information that has also been added to the postmarketing section of the label. The three cases were identified through routine monitoring of VAERS and were reported in children receiving routine pediatric vaccines, including RotaTeq, according to an FDA statement on the Center for Biologics Evaluation and Research Web site.

The three reports to VAERS do not exceed the number of cases that would normally be expected in children, and there is “not a known cause-and-effect relationship between receiving RotaTeq, or any other vaccine, and the occurrence of Kawasaki disease,” the statement said. No changes to the indication for RotaTeq have been made, and no new warnings or precautions have been issued, and “health-care practitioners and parents should remain confident in using RotaTeq.” As of June 8, about 6 million RotaTeq doses had been distributed in the United States, according to the FDA.

The FDA and the Centers for Disease Control and Prevention are continuing to monitor the safety of all vaccines, and encourage health care providers to report to VAERS any cases of Kawasaki disease and other serious adverse events in recipients of RotaTeq and other vaccines.

The CDC's Vaccine Safety Datalink (VSD) project also is monitoring for Kawasaki disease in RotaTeq vaccinees. In early June, the VSD project reported one case of Kawasaki disease that occurred within 30 days of RotaTeq vaccination, which was not confirmed.

This case is among 65,000 RotaTeq doses administered to children under age 1 year who are enrolled in the project, which is monitoring the safety of vaccines among patients enrolled in eight managed care organizations.

Kawasaki disease affects about 4,000 children annually in the United States; 80% are younger than age 5. RotaTeq is manufactured by Merck.

Several postmarketing reports of Kawasaki disease in recipients of the RotaTeq vaccine have prompted changes in the vaccine's label, but to date there is no known cause-and-effect relationship between the vaccine and these reports, according to the Food and Drug Administration.

Last month, the FDA approved the labeling changes, which add information to the adverse reactions and postmarketing sections of the vaccine's label. The information added includes six cases of Kawasaki disease that were observed in the phase III clinical trial of RotaTeq—five cases among 36,150 infants who received RotaTeq and one case among 35,536 infants who received the placebo.

There have been three additional cases of Kawasaki disease reported to the Vaccine Adverse Event Reporting System (VAERS) since RotaTeq was approved in February 2006 for preventing rotavirus infection—information that has also been added to the postmarketing section of the label. The three cases were identified through routine monitoring of VAERS and were reported in children receiving routine pediatric vaccines, including RotaTeq, according to an FDA statement on the Center for Biologics Evaluation and Research Web site.

The three reports to VAERS do not exceed the number of cases that would normally be expected in children, and there is “not a known cause-and-effect relationship between receiving RotaTeq, or any other vaccine, and the occurrence of Kawasaki disease,” the statement said. No changes to the indication for RotaTeq have been made, and no new warnings or precautions have been issued, and “health-care practitioners and parents should remain confident in using RotaTeq.” As of June 8, about 6 million RotaTeq doses had been distributed in the United States, according to the FDA.

The FDA and the Centers for Disease Control and Prevention are continuing to monitor the safety of all vaccines, and encourage health care providers to report to VAERS any cases of Kawasaki disease and other serious adverse events in recipients of RotaTeq and other vaccines.

The CDC's Vaccine Safety Datalink (VSD) project also is monitoring for Kawasaki disease in RotaTeq vaccinees. In early June, the VSD project reported one case of Kawasaki disease that occurred within 30 days of RotaTeq vaccination, which was not confirmed.

This case is among 65,000 RotaTeq doses administered to children under age 1 year who are enrolled in the project, which is monitoring the safety of vaccines among patients enrolled in eight managed care organizations.

Kawasaki disease affects about 4,000 children annually in the United States; 80% are younger than age 5. RotaTeq is manufactured by Merck.

Several postmarketing reports of Kawasaki disease in recipients of the RotaTeq vaccine have prompted changes in the vaccine's label, but to date there is no known cause-and-effect relationship between the vaccine and these reports, according to the Food and Drug Administration.

Last month, the FDA approved the labeling changes, which add information to the adverse reactions and postmarketing sections of the vaccine's label. The information added includes six cases of Kawasaki disease that were observed in the phase III clinical trial of RotaTeq—five cases among 36,150 infants who received RotaTeq and one case among 35,536 infants who received the placebo.

There have been three additional cases of Kawasaki disease reported to the Vaccine Adverse Event Reporting System (VAERS) since RotaTeq was approved in February 2006 for preventing rotavirus infection—information that has also been added to the postmarketing section of the label. The three cases were identified through routine monitoring of VAERS and were reported in children receiving routine pediatric vaccines, including RotaTeq, according to an FDA statement on the Center for Biologics Evaluation and Research Web site.

The three reports to VAERS do not exceed the number of cases that would normally be expected in children, and there is “not a known cause-and-effect relationship between receiving RotaTeq, or any other vaccine, and the occurrence of Kawasaki disease,” the statement said. No changes to the indication for RotaTeq have been made, and no new warnings or precautions have been issued, and “health-care practitioners and parents should remain confident in using RotaTeq.” As of June 8, about 6 million RotaTeq doses had been distributed in the United States, according to the FDA.

The FDA and the Centers for Disease Control and Prevention are continuing to monitor the safety of all vaccines, and encourage health care providers to report to VAERS any cases of Kawasaki disease and other serious adverse events in recipients of RotaTeq and other vaccines.

The CDC's Vaccine Safety Datalink (VSD) project also is monitoring for Kawasaki disease in RotaTeq vaccinees. In early June, the VSD project reported one case of Kawasaki disease that occurred within 30 days of RotaTeq vaccination, which was not confirmed.

This case is among 65,000 RotaTeq doses administered to children under age 1 year who are enrolled in the project, which is monitoring the safety of vaccines among patients enrolled in eight managed care organizations.

Kawasaki disease affects about 4,000 children annually in the United States; 80% are younger than age 5. RotaTeq is manufactured by Merck.