Elizabeth Mechcatie

Last month, the Food and Drug Administration approved an injectable formulation of ibandronate, the first intravenous treatment for osteoporosis to become available and the first bisphosphonate administered once every 3 months.

The approved dose is 3 mg, administered intravenously over 15–30 seconds, by a health care professional, once every 3 months. Ibandronate is the third such formulation approved by the FDA; the first, a daily 2.5-mg formulation approved in 2003, was never marketed because of the availability of more convenient weekly bisphosphonate formulations that were already available at that time. A monthly oral formulation of ibandronate (150 mg) was approved and marketed almost a year ago. Like the monthly formulation, the IV formulation will be marketed under the trade name Boniva, by Hoffmann-La Roche. It will be available “early this year,” according to a press release announcing the approval. At press time, the company had not provided information on its cost.

Bypassing the esophagus and stomach—eliminating the need to sit upright without drinking or eating for 30–60 minutes after taking an oral bisphosphonate that is required to reduce the risk of esophagitis and gastritis—is perhaps the most obvious advantage of the IV formulation, said Dr. Robert Recker, director of the Creighton University Osteoporosis Research Center, Omaha, Neb.

Injectable ibandronate can also be used for patients who cannot swallow well, and having the patient come to the office once every 3 months for an injection assures compliance and may be more convenient for patients, added Dr. Recker, who is also professor of medicine and chief of the division of endocrinology at the University. He is a consultant to Roche, and to manufacturers of other osteoporosis therapies, and has conducted clinical trials funded by all these companies.

Dr. Recker was among the investigators in the DIVA (the Dosing Intravenous Administration) study, a randomized, double-blind multinational “noninferiority” study of 1,358 women with postmenopausal osteoporosis. The study compared 2.5 mg of ibandronate daily with the injectable formulation once every 3 months; at 1 year, bone mineral density (BMD) of the lumbar spine had increased by a mean of 4.5% among those on the IV treatment vs. a mean of 3.5% among those on daily therapy, a highly statistically significant difference. Increases in the total hip, femoral neck and trochanter BMD were also greater among those on IV ibandronate.

Because the 2.5-mg daily formulation has already been shown to reduce the risk of new vertebral fractures over 3 years in studies that were the basis of that formulation's approval, antifracture efficacy data on IV ibandronate were not required for approval.

Overall safety and tolerability of IV ibandronate was similar to that associated with the daily oral dose in the DIVA study, with arthralgia, abdominal pain, and back pain among the most commonly reported side effects. Some patients experience a mild flu-like syndrome with the first injection, which, if necessary, is easily suppressed with aspirin, acetaminophen, or an NSAID, although some people do not need to take anything, Dr. Recker said.

Because IV bisphosphonates have been associated with renal toxicity, serum creatinine should be checked before each dose, and patients with severe renal impairment should not receive the drug, according to the product's label (package insert), approved by the FDA. No cases of acute renal failure were reported in controlled trials where IV Boniva was administered over 15–30 seconds. Like other bisphosphonates, ibandronate inhibits osteoclast-mediated bone resorption, reducing the elevated rate of bone turnover. The other two bisphosphonates approved for treating postmenopausal osteoporosis are alendronate (Fosamax) and risedronate (Actonel), which are administered weekly, and are also approved for prevention of osteoporosis.

To get the most benefits from bisphosphonates, Dr. Recker stressed taking a daily absorbable calcium supplement of more than 1,200 mg of calcium a day taken in divided doses with meals, and a vitamin D supplement. He recommends 1,000 mg of vitamin D₃ every day, not vitamin D₂, which is in most supplements.

Last month, the Food and Drug Administration approved an injectable formulation of ibandronate, the first intravenous treatment for osteoporosis to become available and the first bisphosphonate administered once every 3 months.

The approved dose is 3 mg, administered intravenously over 15–30 seconds, by a health care professional, once every 3 months. Ibandronate is the third such formulation approved by the FDA; the first, a daily 2.5-mg formulation approved in 2003, was never marketed because of the availability of more convenient weekly bisphosphonate formulations that were already available at that time. A monthly oral formulation of ibandronate (150 mg) was approved and marketed almost a year ago. Like the monthly formulation, the IV formulation will be marketed under the trade name Boniva, by Hoffmann-La Roche. It will be available “early this year,” according to a press release announcing the approval. At press time, the company had not provided information on its cost.

Bypassing the esophagus and stomach—eliminating the need to sit upright without drinking or eating for 30–60 minutes after taking an oral bisphosphonate that is required to reduce the risk of esophagitis and gastritis—is perhaps the most obvious advantage of the IV formulation, said Dr. Robert Recker, director of the Creighton University Osteoporosis Research Center, Omaha, Neb.

Injectable ibandronate can also be used for patients who cannot swallow well, and having the patient come to the office once every 3 months for an injection assures compliance and may be more convenient for patients, added Dr. Recker, who is also professor of medicine and chief of the division of endocrinology at the University. He is a consultant to Roche, and to manufacturers of other osteoporosis therapies, and has conducted clinical trials funded by all these companies.

Dr. Recker was among the investigators in the DIVA (the Dosing Intravenous Administration) study, a randomized, double-blind multinational “noninferiority” study of 1,358 women with postmenopausal osteoporosis. The study compared 2.5 mg of ibandronate daily with the injectable formulation once every 3 months; at 1 year, bone mineral density (BMD) of the lumbar spine had increased by a mean of 4.5% among those on the IV treatment vs. a mean of 3.5% among those on daily therapy, a highly statistically significant difference. Increases in the total hip, femoral neck and trochanter BMD were also greater among those on IV ibandronate.

Because the 2.5-mg daily formulation has already been shown to reduce the risk of new vertebral fractures over 3 years in studies that were the basis of that formulation's approval, antifracture efficacy data on IV ibandronate were not required for approval.

Overall safety and tolerability of IV ibandronate was similar to that associated with the daily oral dose in the DIVA study, with arthralgia, abdominal pain, and back pain among the most commonly reported side effects. Some patients experience a mild flu-like syndrome with the first injection, which, if necessary, is easily suppressed with aspirin, acetaminophen, or an NSAID, although some people do not need to take anything, Dr. Recker said.

Because IV bisphosphonates have been associated with renal toxicity, serum creatinine should be checked before each dose, and patients with severe renal impairment should not receive the drug, according to the product's label (package insert), approved by the FDA. No cases of acute renal failure were reported in controlled trials where IV Boniva was administered over 15–30 seconds. Like other bisphosphonates, ibandronate inhibits osteoclast-mediated bone resorption, reducing the elevated rate of bone turnover. The other two bisphosphonates approved for treating postmenopausal osteoporosis are alendronate (Fosamax) and risedronate (Actonel), which are administered weekly, and are also approved for prevention of osteoporosis.

To get the most benefits from bisphosphonates, Dr. Recker stressed taking a daily absorbable calcium supplement of more than 1,200 mg of calcium a day taken in divided doses with meals, and a vitamin D supplement. He recommends 1,000 mg of vitamin D₃ every day, not vitamin D₂, which is in most supplements.

Last month, the Food and Drug Administration approved an injectable formulation of ibandronate, the first intravenous treatment for osteoporosis to become available and the first bisphosphonate administered once every 3 months.

The approved dose is 3 mg, administered intravenously over 15–30 seconds, by a health care professional, once every 3 months. Ibandronate is the third such formulation approved by the FDA; the first, a daily 2.5-mg formulation approved in 2003, was never marketed because of the availability of more convenient weekly bisphosphonate formulations that were already available at that time. A monthly oral formulation of ibandronate (150 mg) was approved and marketed almost a year ago. Like the monthly formulation, the IV formulation will be marketed under the trade name Boniva, by Hoffmann-La Roche. It will be available “early this year,” according to a press release announcing the approval. At press time, the company had not provided information on its cost.

Bypassing the esophagus and stomach—eliminating the need to sit upright without drinking or eating for 30–60 minutes after taking an oral bisphosphonate that is required to reduce the risk of esophagitis and gastritis—is perhaps the most obvious advantage of the IV formulation, said Dr. Robert Recker, director of the Creighton University Osteoporosis Research Center, Omaha, Neb.

Injectable ibandronate can also be used for patients who cannot swallow well, and having the patient come to the office once every 3 months for an injection assures compliance and may be more convenient for patients, added Dr. Recker, who is also professor of medicine and chief of the division of endocrinology at the University. He is a consultant to Roche, and to manufacturers of other osteoporosis therapies, and has conducted clinical trials funded by all these companies.

Dr. Recker was among the investigators in the DIVA (the Dosing Intravenous Administration) study, a randomized, double-blind multinational “noninferiority” study of 1,358 women with postmenopausal osteoporosis. The study compared 2.5 mg of ibandronate daily with the injectable formulation once every 3 months; at 1 year, bone mineral density (BMD) of the lumbar spine had increased by a mean of 4.5% among those on the IV treatment vs. a mean of 3.5% among those on daily therapy, a highly statistically significant difference. Increases in the total hip, femoral neck and trochanter BMD were also greater among those on IV ibandronate.

Because the 2.5-mg daily formulation has already been shown to reduce the risk of new vertebral fractures over 3 years in studies that were the basis of that formulation's approval, antifracture efficacy data on IV ibandronate were not required for approval.

Overall safety and tolerability of IV ibandronate was similar to that associated with the daily oral dose in the DIVA study, with arthralgia, abdominal pain, and back pain among the most commonly reported side effects. Some patients experience a mild flu-like syndrome with the first injection, which, if necessary, is easily suppressed with aspirin, acetaminophen, or an NSAID, although some people do not need to take anything, Dr. Recker said.

Because IV bisphosphonates have been associated with renal toxicity, serum creatinine should be checked before each dose, and patients with severe renal impairment should not receive the drug, according to the product's label (package insert), approved by the FDA. No cases of acute renal failure were reported in controlled trials where IV Boniva was administered over 15–30 seconds. Like other bisphosphonates, ibandronate inhibits osteoclast-mediated bone resorption, reducing the elevated rate of bone turnover. The other two bisphosphonates approved for treating postmenopausal osteoporosis are alendronate (Fosamax) and risedronate (Actonel), which are administered weekly, and are also approved for prevention of osteoporosis.

To get the most benefits from bisphosphonates, Dr. Recker stressed taking a daily absorbable calcium supplement of more than 1,200 mg of calcium a day taken in divided doses with meals, and a vitamin D supplement. He recommends 1,000 mg of vitamin D₃ every day, not vitamin D₂, which is in most supplements.

Preliminary results from two large ongoing epidemiologic studies evaluating the safety of the Ortho Evra contraceptive patch provided conflicting data on whether the risk of thrombotic events might be greater with the patch than with oral contraceptive pills.

Last month, the manufacturer, Ortho Women's Health and Urology, announced preliminary results of the two studies, which are comparing thrombotic event rates in women on Ortho Evra and women on an oral contraceptive pill containing norgestimate with 35 mcg of ethinyl estradiol. One study found the incidence of nonfatal thrombotic events was about the same among users of Ortho Evra and those on the comparator oral contraceptive. But in the second, the incidence of nonfatal thrombotic events was twice as high than among those on the comparator.

However, these data are preliminary and need to be evaluated further, and are not resulting in any changes to the label or any regulatory actions or specific recommendations on the use of the patch, Dr. Daniel Shames of the Food and Drug Administration emphasized in an FDA-sponsored teleconference, held the day after the manufacturer released these results.

The studies are using data from large medical claims insurance databases in the United States; these are the first results to become available. Dr. Shames, director of the division of reproductive and urologic drug products, in the FDA's Center for Drug Evaluation and Research, Rockville, Md., said that more precise information could be available by May.

Preliminary results from two large ongoing epidemiologic studies evaluating the safety of the Ortho Evra contraceptive patch provided conflicting data on whether the risk of thrombotic events might be greater with the patch than with oral contraceptive pills.

Last month, the manufacturer, Ortho Women's Health and Urology, announced preliminary results of the two studies, which are comparing thrombotic event rates in women on Ortho Evra and women on an oral contraceptive pill containing norgestimate with 35 mcg of ethinyl estradiol. One study found the incidence of nonfatal thrombotic events was about the same among users of Ortho Evra and those on the comparator oral contraceptive. But in the second, the incidence of nonfatal thrombotic events was twice as high than among those on the comparator.

However, these data are preliminary and need to be evaluated further, and are not resulting in any changes to the label or any regulatory actions or specific recommendations on the use of the patch, Dr. Daniel Shames of the Food and Drug Administration emphasized in an FDA-sponsored teleconference, held the day after the manufacturer released these results.

The studies are using data from large medical claims insurance databases in the United States; these are the first results to become available. Dr. Shames, director of the division of reproductive and urologic drug products, in the FDA's Center for Drug Evaluation and Research, Rockville, Md., said that more precise information could be available by May.

Preliminary results from two large ongoing epidemiologic studies evaluating the safety of the Ortho Evra contraceptive patch provided conflicting data on whether the risk of thrombotic events might be greater with the patch than with oral contraceptive pills.

Last month, the manufacturer, Ortho Women's Health and Urology, announced preliminary results of the two studies, which are comparing thrombotic event rates in women on Ortho Evra and women on an oral contraceptive pill containing norgestimate with 35 mcg of ethinyl estradiol. One study found the incidence of nonfatal thrombotic events was about the same among users of Ortho Evra and those on the comparator oral contraceptive. But in the second, the incidence of nonfatal thrombotic events was twice as high than among those on the comparator.

However, these data are preliminary and need to be evaluated further, and are not resulting in any changes to the label or any regulatory actions or specific recommendations on the use of the patch, Dr. Daniel Shames of the Food and Drug Administration emphasized in an FDA-sponsored teleconference, held the day after the manufacturer released these results.

The studies are using data from large medical claims insurance databases in the United States; these are the first results to become available. Dr. Shames, director of the division of reproductive and urologic drug products, in the FDA's Center for Drug Evaluation and Research, Rockville, Md., said that more precise information could be available by May.

GAITHERSBURG, MD. — A federal advisory panel has supported approval of a transdermal methylphenidate patch for treating attention-deficit hyperactivity disorder in children—with a caveat.

Because of the patch's potential to cause sensitization to methylphenidate, the Food and Drug Administration's Psychopharmacologic Drugs Advisory Committee agreed that an approval should include a warning about this link.

The possibility of sensitization elicited concern among panel members, because a patient who becomes sensitized can never take methylphenidate in any form again.

At a meeting last month, the committee unanimously agreed that the patch was effective for treating ADHD in children aged 6–11 years. That is the indication proposed by Shire Pharmaceuticals Inc. and Noven Pharmaceuticals Inc., the companies that codeveloped it.

In addition, the panel voted 11–1 against an overt restriction that would limit the use of the patch to children who are unable to take oral formulations. Instead, it supported the idea of including language in the label advising prescribers to consider other treatment options that do not pose the same risk of sensitization before considering the transdermal formulation.

Dr. Thomas Laughren, director of the FDA's division of psychiatry products in Rockville, Md., said such wording could take the same approach as language in a section of the label for the atypical antipsychotic ziprasidone (Geodon). Unlike other atypicals on the market, the indications and usage section in ziprasidone's label (or package insert) includes the statement: “When deciding among the alternative treatments available for this condition, the prescriber should consider the finding of ziprasidone's greater capacity to prolong the QT/QTc interval compared to several other antipsychotic drugs.”

The frequency of sensitization in people treated with the patch is uncertain, based on the data available. In trials, there was one report of an allergic reaction in a patient who stopped using the patch because of irritation at the site of the patch that reappeared at the same site after starting on oral methylphenidate, a sign of contact sensitization, said Dr. Raymond Pratt, vice president of clinical development at Shire. The oral medication was then discontinued. The frequency of this kind of reaction is difficult to quantify, he told the panel.

Another concern was how a physician could distinguish between local skin irritation and signs of sensitization, which FDA officials said would be explained in the label.

The panel chair, Dr. Wayne Goodman, said he would vote in favor of safety but recommended that a warning be included in the label until more data are available on this issue. The difficulty in predicting prevalence was troubling, and he and other panel members supported postmarketing surveillance of children treated with the patch to resolve this issue, said Dr. Goodman, chair of the department of psychiatry at the University of Florida, Gainesville.

Dr. Daniel Pine, the panelist who voted in favor of restricting the indication to children for whom oral methylphenidate is not an option, said he was satisfied with the efficacy data.

However, language similar to that in the ziprasidone label would be too weak, and it would be better to err on the side of caution. It would be a “potential disaster” if a proportion of patients with ADHD could not take methylphenidate, remarked Dr. Pine, chief of child and adolescent research in the mood and anxiety disorders program at the National Institute of Mental Health, Bethesda, Md.

If approved, the thin, transparent patch will be available in 10-mg, 16-mg, 20-mg, and 27-mg strengths, providing dose ranges over 9 hours that are similar to the oral sustained formulation of methylphenidate, according to Shire.

The manufacturers submitted an application for approval in 2002, but in 2003 the FDA decided not to approve the patch because of concerns over excessive methylphenidate exposure at inappropriate times and an unacceptable safety profile, which included a high rate of insomnia, anorexia, and weight loss associated with the patch, based on studies in which it was worn for 12 hours. The company then conducted studies of the patch with a 9-hour wear time and resubmitted the application for approval in June.

In the two studies of children aged 6–12 years with ADHD—a 2-day laboratory classroom study of 93 children and a pivotal multicenter outpatient study of 274 children that compared the patch with Concerta and placebo over 7 weeks—significant improvements in behavior were seen within 2 hours of application of the patch (left on for 9 hours) and persisted for 3 hours after removal, according to Shire. About 55% of patients developed some skin irritation at the patch site, but there were few discontinuations because of application site reactions, Dr. Pratt said.

GAITHERSBURG, MD. — A federal advisory panel has supported approval of a transdermal methylphenidate patch for treating attention-deficit hyperactivity disorder in children—with a caveat.

Because of the patch's potential to cause sensitization to methylphenidate, the Food and Drug Administration's Psychopharmacologic Drugs Advisory Committee agreed that an approval should include a warning about this link.

The possibility of sensitization elicited concern among panel members, because a patient who becomes sensitized can never take methylphenidate in any form again.

At a meeting last month, the committee unanimously agreed that the patch was effective for treating ADHD in children aged 6–11 years. That is the indication proposed by Shire Pharmaceuticals Inc. and Noven Pharmaceuticals Inc., the companies that codeveloped it.

In addition, the panel voted 11–1 against an overt restriction that would limit the use of the patch to children who are unable to take oral formulations. Instead, it supported the idea of including language in the label advising prescribers to consider other treatment options that do not pose the same risk of sensitization before considering the transdermal formulation.

Dr. Thomas Laughren, director of the FDA's division of psychiatry products in Rockville, Md., said such wording could take the same approach as language in a section of the label for the atypical antipsychotic ziprasidone (Geodon). Unlike other atypicals on the market, the indications and usage section in ziprasidone's label (or package insert) includes the statement: “When deciding among the alternative treatments available for this condition, the prescriber should consider the finding of ziprasidone's greater capacity to prolong the QT/QTc interval compared to several other antipsychotic drugs.”

The frequency of sensitization in people treated with the patch is uncertain, based on the data available. In trials, there was one report of an allergic reaction in a patient who stopped using the patch because of irritation at the site of the patch that reappeared at the same site after starting on oral methylphenidate, a sign of contact sensitization, said Dr. Raymond Pratt, vice president of clinical development at Shire. The oral medication was then discontinued. The frequency of this kind of reaction is difficult to quantify, he told the panel.

Another concern was how a physician could distinguish between local skin irritation and signs of sensitization, which FDA officials said would be explained in the label.

The panel chair, Dr. Wayne Goodman, said he would vote in favor of safety but recommended that a warning be included in the label until more data are available on this issue. The difficulty in predicting prevalence was troubling, and he and other panel members supported postmarketing surveillance of children treated with the patch to resolve this issue, said Dr. Goodman, chair of the department of psychiatry at the University of Florida, Gainesville.

Dr. Daniel Pine, the panelist who voted in favor of restricting the indication to children for whom oral methylphenidate is not an option, said he was satisfied with the efficacy data.

However, language similar to that in the ziprasidone label would be too weak, and it would be better to err on the side of caution. It would be a “potential disaster” if a proportion of patients with ADHD could not take methylphenidate, remarked Dr. Pine, chief of child and adolescent research in the mood and anxiety disorders program at the National Institute of Mental Health, Bethesda, Md.

If approved, the thin, transparent patch will be available in 10-mg, 16-mg, 20-mg, and 27-mg strengths, providing dose ranges over 9 hours that are similar to the oral sustained formulation of methylphenidate, according to Shire.

The manufacturers submitted an application for approval in 2002, but in 2003 the FDA decided not to approve the patch because of concerns over excessive methylphenidate exposure at inappropriate times and an unacceptable safety profile, which included a high rate of insomnia, anorexia, and weight loss associated with the patch, based on studies in which it was worn for 12 hours. The company then conducted studies of the patch with a 9-hour wear time and resubmitted the application for approval in June.

In the two studies of children aged 6–12 years with ADHD—a 2-day laboratory classroom study of 93 children and a pivotal multicenter outpatient study of 274 children that compared the patch with Concerta and placebo over 7 weeks—significant improvements in behavior were seen within 2 hours of application of the patch (left on for 9 hours) and persisted for 3 hours after removal, according to Shire. About 55% of patients developed some skin irritation at the patch site, but there were few discontinuations because of application site reactions, Dr. Pratt said.

GAITHERSBURG, MD. — A federal advisory panel has supported approval of a transdermal methylphenidate patch for treating attention-deficit hyperactivity disorder in children—with a caveat.

Because of the patch's potential to cause sensitization to methylphenidate, the Food and Drug Administration's Psychopharmacologic Drugs Advisory Committee agreed that an approval should include a warning about this link.

The possibility of sensitization elicited concern among panel members, because a patient who becomes sensitized can never take methylphenidate in any form again.

At a meeting last month, the committee unanimously agreed that the patch was effective for treating ADHD in children aged 6–11 years. That is the indication proposed by Shire Pharmaceuticals Inc. and Noven Pharmaceuticals Inc., the companies that codeveloped it.

In addition, the panel voted 11–1 against an overt restriction that would limit the use of the patch to children who are unable to take oral formulations. Instead, it supported the idea of including language in the label advising prescribers to consider other treatment options that do not pose the same risk of sensitization before considering the transdermal formulation.

Dr. Thomas Laughren, director of the FDA's division of psychiatry products in Rockville, Md., said such wording could take the same approach as language in a section of the label for the atypical antipsychotic ziprasidone (Geodon). Unlike other atypicals on the market, the indications and usage section in ziprasidone's label (or package insert) includes the statement: “When deciding among the alternative treatments available for this condition, the prescriber should consider the finding of ziprasidone's greater capacity to prolong the QT/QTc interval compared to several other antipsychotic drugs.”

The frequency of sensitization in people treated with the patch is uncertain, based on the data available. In trials, there was one report of an allergic reaction in a patient who stopped using the patch because of irritation at the site of the patch that reappeared at the same site after starting on oral methylphenidate, a sign of contact sensitization, said Dr. Raymond Pratt, vice president of clinical development at Shire. The oral medication was then discontinued. The frequency of this kind of reaction is difficult to quantify, he told the panel.

Another concern was how a physician could distinguish between local skin irritation and signs of sensitization, which FDA officials said would be explained in the label.

The panel chair, Dr. Wayne Goodman, said he would vote in favor of safety but recommended that a warning be included in the label until more data are available on this issue. The difficulty in predicting prevalence was troubling, and he and other panel members supported postmarketing surveillance of children treated with the patch to resolve this issue, said Dr. Goodman, chair of the department of psychiatry at the University of Florida, Gainesville.

Dr. Daniel Pine, the panelist who voted in favor of restricting the indication to children for whom oral methylphenidate is not an option, said he was satisfied with the efficacy data.

However, language similar to that in the ziprasidone label would be too weak, and it would be better to err on the side of caution. It would be a “potential disaster” if a proportion of patients with ADHD could not take methylphenidate, remarked Dr. Pine, chief of child and adolescent research in the mood and anxiety disorders program at the National Institute of Mental Health, Bethesda, Md.

If approved, the thin, transparent patch will be available in 10-mg, 16-mg, 20-mg, and 27-mg strengths, providing dose ranges over 9 hours that are similar to the oral sustained formulation of methylphenidate, according to Shire.

The manufacturers submitted an application for approval in 2002, but in 2003 the FDA decided not to approve the patch because of concerns over excessive methylphenidate exposure at inappropriate times and an unacceptable safety profile, which included a high rate of insomnia, anorexia, and weight loss associated with the patch, based on studies in which it was worn for 12 hours. The company then conducted studies of the patch with a 9-hour wear time and resubmitted the application for approval in June.

In the two studies of children aged 6–12 years with ADHD—a 2-day laboratory classroom study of 93 children and a pivotal multicenter outpatient study of 274 children that compared the patch with Concerta and placebo over 7 weeks—significant improvements in behavior were seen within 2 hours of application of the patch (left on for 9 hours) and persisted for 3 hours after removal, according to Shire. About 55% of patients developed some skin irritation at the patch site, but there were few discontinuations because of application site reactions, Dr. Pratt said.

BETHESDA, MD. — With timely diagnosis and treatment, the prognosis can be good for women with pheochromocytoma during pregnancy, Dr. Henri Timmers said at an international symposium on pheochromocytoma sponsored by the National Institutes of Health.

His conclusion, based on a literature review of more than 100 cases, also found that maternal morbidity is high when diagnosis is delayed, said Dr. Timmers, of the department of endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

Pheochromocytoma affects an estimated 1/50,000 full-term pregnancies and is associated with high maternal and fetal morbidity and mortality. Pheochromocytoma during pregnancy is often missed because it can mimic preeclampsia, delaying diagnosis and appropriate treatment, Dr. Timmers noted.

He and associates found a total of 174 reports of histology-confirmed cases of pheochromocytoma during pregnancy, in a PubMed database search for case reports in English. The mean age of the women was 28 years, 7% had previously been diagnosed with pheochromocytoma and 17% had been previously diagnosed with hypertension; 61% had been pregnant before and 14% had been previously diagnosed with pregnancy-induced hypertension.

In 73% of cases, the diagnosis of pheochromocytoma was made before delivery, with the remainder diagnosed postpartum (17%) or postmortem (10%).

Nearly 90% of the patients were hypertensive, but in only 42% of the cases was presentation typical for pheochromocytoma, where hypertension is usually accompanied by headache, palpitations, or sweating. In 25% of the cases, presentation was a hypertensive emergency, which included cases of severe pulmonary edema, he said.

In 31% of the cases, the initial diagnosis was incorrect, with almost half of the incorrectly diagnosed patients presenting with a severe cardiovascular complication; of these 24 patients, 10 patients died. Fetal and neonatal mortality was 22%. Overall maternal mortality was about 14%, but it was markedly higher in different subgroups: It was 38% among the women who were incorrectly diagnosed and 49% among those with a cardiovascular emergency.

The biochemical test with the greatest diagnostic sensitivity in this population was urinary metanephrines, with a sensitivity of 98%; the lowest sensitivity was for plasma catecholamines (91%). The sensitivity of MRI was 95%.

Surgery was performed in 69 of these patients, either before 24 weeks gestation or during a cesarean section; in 68 patients, surgery was performed post partum.

During the discussion period, moderator Dr. William Manger, of New York University and the chairman of the National Hypertension Association, New York City, said that pheochromocytoma, though rare, is a devastating condition and should be routinely considered in pregnant women with hypertension.

BETHESDA, MD. — With timely diagnosis and treatment, the prognosis can be good for women with pheochromocytoma during pregnancy, Dr. Henri Timmers said at an international symposium on pheochromocytoma sponsored by the National Institutes of Health.

His conclusion, based on a literature review of more than 100 cases, also found that maternal morbidity is high when diagnosis is delayed, said Dr. Timmers, of the department of endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

Pheochromocytoma affects an estimated 1/50,000 full-term pregnancies and is associated with high maternal and fetal morbidity and mortality. Pheochromocytoma during pregnancy is often missed because it can mimic preeclampsia, delaying diagnosis and appropriate treatment, Dr. Timmers noted.

He and associates found a total of 174 reports of histology-confirmed cases of pheochromocytoma during pregnancy, in a PubMed database search for case reports in English. The mean age of the women was 28 years, 7% had previously been diagnosed with pheochromocytoma and 17% had been previously diagnosed with hypertension; 61% had been pregnant before and 14% had been previously diagnosed with pregnancy-induced hypertension.

In 73% of cases, the diagnosis of pheochromocytoma was made before delivery, with the remainder diagnosed postpartum (17%) or postmortem (10%).

Nearly 90% of the patients were hypertensive, but in only 42% of the cases was presentation typical for pheochromocytoma, where hypertension is usually accompanied by headache, palpitations, or sweating. In 25% of the cases, presentation was a hypertensive emergency, which included cases of severe pulmonary edema, he said.

In 31% of the cases, the initial diagnosis was incorrect, with almost half of the incorrectly diagnosed patients presenting with a severe cardiovascular complication; of these 24 patients, 10 patients died. Fetal and neonatal mortality was 22%. Overall maternal mortality was about 14%, but it was markedly higher in different subgroups: It was 38% among the women who were incorrectly diagnosed and 49% among those with a cardiovascular emergency.

The biochemical test with the greatest diagnostic sensitivity in this population was urinary metanephrines, with a sensitivity of 98%; the lowest sensitivity was for plasma catecholamines (91%). The sensitivity of MRI was 95%.

Surgery was performed in 69 of these patients, either before 24 weeks gestation or during a cesarean section; in 68 patients, surgery was performed post partum.

During the discussion period, moderator Dr. William Manger, of New York University and the chairman of the National Hypertension Association, New York City, said that pheochromocytoma, though rare, is a devastating condition and should be routinely considered in pregnant women with hypertension.

BETHESDA, MD. — With timely diagnosis and treatment, the prognosis can be good for women with pheochromocytoma during pregnancy, Dr. Henri Timmers said at an international symposium on pheochromocytoma sponsored by the National Institutes of Health.

His conclusion, based on a literature review of more than 100 cases, also found that maternal morbidity is high when diagnosis is delayed, said Dr. Timmers, of the department of endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

Pheochromocytoma affects an estimated 1/50,000 full-term pregnancies and is associated with high maternal and fetal morbidity and mortality. Pheochromocytoma during pregnancy is often missed because it can mimic preeclampsia, delaying diagnosis and appropriate treatment, Dr. Timmers noted.

He and associates found a total of 174 reports of histology-confirmed cases of pheochromocytoma during pregnancy, in a PubMed database search for case reports in English. The mean age of the women was 28 years, 7% had previously been diagnosed with pheochromocytoma and 17% had been previously diagnosed with hypertension; 61% had been pregnant before and 14% had been previously diagnosed with pregnancy-induced hypertension.

In 73% of cases, the diagnosis of pheochromocytoma was made before delivery, with the remainder diagnosed postpartum (17%) or postmortem (10%).

Nearly 90% of the patients were hypertensive, but in only 42% of the cases was presentation typical for pheochromocytoma, where hypertension is usually accompanied by headache, palpitations, or sweating. In 25% of the cases, presentation was a hypertensive emergency, which included cases of severe pulmonary edema, he said.

In 31% of the cases, the initial diagnosis was incorrect, with almost half of the incorrectly diagnosed patients presenting with a severe cardiovascular complication; of these 24 patients, 10 patients died. Fetal and neonatal mortality was 22%. Overall maternal mortality was about 14%, but it was markedly higher in different subgroups: It was 38% among the women who were incorrectly diagnosed and 49% among those with a cardiovascular emergency.

The biochemical test with the greatest diagnostic sensitivity in this population was urinary metanephrines, with a sensitivity of 98%; the lowest sensitivity was for plasma catecholamines (91%). The sensitivity of MRI was 95%.

Surgery was performed in 69 of these patients, either before 24 weeks gestation or during a cesarean section; in 68 patients, surgery was performed post partum.

During the discussion period, moderator Dr. William Manger, of New York University and the chairman of the National Hypertension Association, New York City, said that pheochromocytoma, though rare, is a devastating condition and should be routinely considered in pregnant women with hypertension.

BETHESDA, MD. — With timely diagnosis and treatment, the prognosis can be good for women with pheochromocytoma during pregnancy, Dr. Henri Timmers said at an international symposium on pheochromocytoma sponsored by the National Institutes of Health.

His conclusion, based on a literature review of more than 100 cases, also found that maternal morbidity is high when diagnosis is delayed, said Dr. Timmers, of the department of endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

Pheochromocytoma affects an estimated 1/50,000 full-term pregnancies and is associated with high maternal and fetal morbidity and mortality. Pheochromocytoma during pregnancy is often missed because it can mimic preeclampsia, delaying diagnosis and appropriate treatment.

Dr. Timmers and associates found a total of 174 reports of histology-confirmed cases of pheochromocytoma during pregnancy, in a PubMed database search for case reports in English. The mean age of the women was 28 years, 7% had previously been diagnosed with pheochromocytoma and 17% had been previously diagnosed with hypertension; 61% had been pregnant before and 14% had been previously diagnosed with pregnancy-induced hypertension.

In 73% of cases, the diagnosis of pheochromocytoma was made before delivery, with the remainder diagnosed postpartum (17%) or postmortem (10%).

Nearly 90% of the patients were hypertensive, but in only 42% of the cases was presentation typical for pheochromocytoma, where hypertension is usually accompanied by headache, palpitations, or sweating. In 25% of the cases, presentation was a hypertensive emergency, which included cases of severe pulmonary edema, Dr. Timmers said.

In 31% of the cases (54 patients), the initial diagnosis was incorrect, with almost half of the incorrectly diagnosed patients presenting with a severe cardiovascular complication, such as heart failure; of these 24 patients, 10 patients died. Fetal and neonatal mortality was 22%. Overall maternal mortality was about 14%, but it was markedly higher in different subgroups: It was 38% among the women who were incorrectly diagnosed and 49% among those with a cardiovascular emergency.

The biochemical test with the greatest diagnostic sensitivity was urinary metanephrines, with a sensitivity of 98%; the lowest sensitivity was for plasma catecholamines (91%). The sensitivity of MRI was 95%.

Surgery was performed either before 24 weeks' gestation or during a cesarean section in 69 patients. Surgery was performed post partum in 68.

During the discussion, moderator Dr. William Manger, chairman of the National Hypertension Association, New York, said pheochromocytoma, though rare, is devastating and should be routinely considered in pregnant women with hypertension.

BETHESDA, MD. — With timely diagnosis and treatment, the prognosis can be good for women with pheochromocytoma during pregnancy, Dr. Henri Timmers said at an international symposium on pheochromocytoma sponsored by the National Institutes of Health.

His conclusion, based on a literature review of more than 100 cases, also found that maternal morbidity is high when diagnosis is delayed, said Dr. Timmers, of the department of endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

Pheochromocytoma affects an estimated 1/50,000 full-term pregnancies and is associated with high maternal and fetal morbidity and mortality. Pheochromocytoma during pregnancy is often missed because it can mimic preeclampsia, delaying diagnosis and appropriate treatment.

Dr. Timmers and associates found a total of 174 reports of histology-confirmed cases of pheochromocytoma during pregnancy, in a PubMed database search for case reports in English. The mean age of the women was 28 years, 7% had previously been diagnosed with pheochromocytoma and 17% had been previously diagnosed with hypertension; 61% had been pregnant before and 14% had been previously diagnosed with pregnancy-induced hypertension.

In 73% of cases, the diagnosis of pheochromocytoma was made before delivery, with the remainder diagnosed postpartum (17%) or postmortem (10%).

Nearly 90% of the patients were hypertensive, but in only 42% of the cases was presentation typical for pheochromocytoma, where hypertension is usually accompanied by headache, palpitations, or sweating. In 25% of the cases, presentation was a hypertensive emergency, which included cases of severe pulmonary edema, Dr. Timmers said.

In 31% of the cases (54 patients), the initial diagnosis was incorrect, with almost half of the incorrectly diagnosed patients presenting with a severe cardiovascular complication, such as heart failure; of these 24 patients, 10 patients died. Fetal and neonatal mortality was 22%. Overall maternal mortality was about 14%, but it was markedly higher in different subgroups: It was 38% among the women who were incorrectly diagnosed and 49% among those with a cardiovascular emergency.

The biochemical test with the greatest diagnostic sensitivity was urinary metanephrines, with a sensitivity of 98%; the lowest sensitivity was for plasma catecholamines (91%). The sensitivity of MRI was 95%.

Surgery was performed either before 24 weeks' gestation or during a cesarean section in 69 patients. Surgery was performed post partum in 68.

During the discussion, moderator Dr. William Manger, chairman of the National Hypertension Association, New York, said pheochromocytoma, though rare, is devastating and should be routinely considered in pregnant women with hypertension.

BETHESDA, MD. — With timely diagnosis and treatment, the prognosis can be good for women with pheochromocytoma during pregnancy, Dr. Henri Timmers said at an international symposium on pheochromocytoma sponsored by the National Institutes of Health.

His conclusion, based on a literature review of more than 100 cases, also found that maternal morbidity is high when diagnosis is delayed, said Dr. Timmers, of the department of endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

Pheochromocytoma affects an estimated 1/50,000 full-term pregnancies and is associated with high maternal and fetal morbidity and mortality. Pheochromocytoma during pregnancy is often missed because it can mimic preeclampsia, delaying diagnosis and appropriate treatment.

Dr. Timmers and associates found a total of 174 reports of histology-confirmed cases of pheochromocytoma during pregnancy, in a PubMed database search for case reports in English. The mean age of the women was 28 years, 7% had previously been diagnosed with pheochromocytoma and 17% had been previously diagnosed with hypertension; 61% had been pregnant before and 14% had been previously diagnosed with pregnancy-induced hypertension.

In 73% of cases, the diagnosis of pheochromocytoma was made before delivery, with the remainder diagnosed postpartum (17%) or postmortem (10%).

Nearly 90% of the patients were hypertensive, but in only 42% of the cases was presentation typical for pheochromocytoma, where hypertension is usually accompanied by headache, palpitations, or sweating. In 25% of the cases, presentation was a hypertensive emergency, which included cases of severe pulmonary edema, Dr. Timmers said.

In 31% of the cases (54 patients), the initial diagnosis was incorrect, with almost half of the incorrectly diagnosed patients presenting with a severe cardiovascular complication, such as heart failure; of these 24 patients, 10 patients died. Fetal and neonatal mortality was 22%. Overall maternal mortality was about 14%, but it was markedly higher in different subgroups: It was 38% among the women who were incorrectly diagnosed and 49% among those with a cardiovascular emergency.

The biochemical test with the greatest diagnostic sensitivity was urinary metanephrines, with a sensitivity of 98%; the lowest sensitivity was for plasma catecholamines (91%). The sensitivity of MRI was 95%.

Surgery was performed either before 24 weeks' gestation or during a cesarean section in 69 patients. Surgery was performed post partum in 68.

During the discussion, moderator Dr. William Manger, chairman of the National Hypertension Association, New York, said pheochromocytoma, though rare, is devastating and should be routinely considered in pregnant women with hypertension.

BETHESDA, MD. — Sustained, severe hypertension was among the clinical features of pheochromocytoma seen more frequently in patients under age 20, compared with adults, Dr. Marta Barontini said at an international symposium on pheochromocytoma sponsored by the National Institutes of Health.

Familial pheochromocytoma, mainly von Hippel-Lindau (VHL) disease, was also more common in the younger patients, “which may account for the noradrenergic profile” of their presenting symptoms, said Dr. Barontini of the center for endocrine research at the R. Gutiérrez Hospital for Children, Buenos Aires.

These findings were based on a review of 58 patients aged 4–20 (12 boys and 1 girl were younger than age 10; the rest were older), who represented 23% of the 255 pheochromocytoma patients studied at the endocrinology research center during a 40-year period. The purpose of the study was to establish clinical features of pheochromocytoma. Laboratory tests used to make the diagnosis, which was confirmed at the time of surgery, included urinary and plasma catecholamines (epinephrine, norepinephrine, and dopamine), as well as urinary levels of vanillylmandelic acid.

The differences between the clinical signs in the older patients at the center and those in the younger patients were “remarkable,” Dr. Barontini said. Sustained hypertension, headaches, and sweating were among the predominant characteristics seen in the younger patients: 93% had severe sustained hypertension, 7% had paroxysmal hypertension, and none was normotensive. Of the older patients, 69% had severe sustained hypertension, 26% had paroxysmal hypertension, and 5% were normotensive.

Other clinical signs often found in the younger patients were headaches in 95%, sweating in 90%, blurred vision in 80%, and encephalopathy in 65%. Palpitations, present in 35% of the younger patients, and weight loss, in 15%, were less common than they were in adults, she said.

Among the younger patients, 2% had normal norepinephrine levels, 55% had normal epinephrine levels, and 7% had normal urinary vanillylmandelic acid levels.

Of the patients under age 20, 34% had bilateral adrenal pheochromocytoma and 22% had extraadrenal pheochromocytoma. The incidence of both conditions was lower in the older patients.

Among the 58 younger patients, 7 (12%) had a malignant tumor, which was fatal in 4 patients: 1 patient died a few months after surgery and 3 died 8–18 years after surgery. The three patients still alive 5–21 years after surgery include one patient who has hypertension that is treated with four drugs. This patient also has high catecholamine levels and widespread bone metastases, but maintains a good quality of life, Dr. Barontini said.

Familial pheochromocytoma was identified in 36% of those younger than age 20, compared with 22% of the older patients. Genetic testing, which was performed in familial cases, found surprising differences.

VHL disease—an autosomal-dominant neoplasia disorder—had a higher prevalence in the younger population (28%), compared with that in the older patients. Multiple endocrine neoplasia (MEN) type 2a was identified in 2% of the younger patients, MEN type 2b in 2%, neurofibromatosis in 3%, and succinate dehydrogenase subunit B mutations in 2%.

In contrast, the most common mutation among the older patients with familial pheochromocytoma was MEN type 2a, in 15%. Dr. Barontini speculated that the higher incidence of VHL in the younger patients may account for the biochemical and clinical features—the noradrenergic profile—seen in this age group.

BETHESDA, MD. — Sustained, severe hypertension was among the clinical features of pheochromocytoma seen more frequently in patients under age 20, compared with adults, Dr. Marta Barontini said at an international symposium on pheochromocytoma sponsored by the National Institutes of Health.

Familial pheochromocytoma, mainly von Hippel-Lindau (VHL) disease, was also more common in the younger patients, “which may account for the noradrenergic profile” of their presenting symptoms, said Dr. Barontini of the center for endocrine research at the R. Gutiérrez Hospital for Children, Buenos Aires.

These findings were based on a review of 58 patients aged 4–20 (12 boys and 1 girl were younger than age 10; the rest were older), who represented 23% of the 255 pheochromocytoma patients studied at the endocrinology research center during a 40-year period. The purpose of the study was to establish clinical features of pheochromocytoma. Laboratory tests used to make the diagnosis, which was confirmed at the time of surgery, included urinary and plasma catecholamines (epinephrine, norepinephrine, and dopamine), as well as urinary levels of vanillylmandelic acid.

The differences between the clinical signs in the older patients at the center and those in the younger patients were “remarkable,” Dr. Barontini said. Sustained hypertension, headaches, and sweating were among the predominant characteristics seen in the younger patients: 93% had severe sustained hypertension, 7% had paroxysmal hypertension, and none was normotensive. Of the older patients, 69% had severe sustained hypertension, 26% had paroxysmal hypertension, and 5% were normotensive.

Other clinical signs often found in the younger patients were headaches in 95%, sweating in 90%, blurred vision in 80%, and encephalopathy in 65%. Palpitations, present in 35% of the younger patients, and weight loss, in 15%, were less common than they were in adults, she said.

Among the younger patients, 2% had normal norepinephrine levels, 55% had normal epinephrine levels, and 7% had normal urinary vanillylmandelic acid levels.

Of the patients under age 20, 34% had bilateral adrenal pheochromocytoma and 22% had extraadrenal pheochromocytoma. The incidence of both conditions was lower in the older patients.

Among the 58 younger patients, 7 (12%) had a malignant tumor, which was fatal in 4 patients: 1 patient died a few months after surgery and 3 died 8–18 years after surgery. The three patients still alive 5–21 years after surgery include one patient who has hypertension that is treated with four drugs. This patient also has high catecholamine levels and widespread bone metastases, but maintains a good quality of life, Dr. Barontini said.

Familial pheochromocytoma was identified in 36% of those younger than age 20, compared with 22% of the older patients. Genetic testing, which was performed in familial cases, found surprising differences.

VHL disease—an autosomal-dominant neoplasia disorder—had a higher prevalence in the younger population (28%), compared with that in the older patients. Multiple endocrine neoplasia (MEN) type 2a was identified in 2% of the younger patients, MEN type 2b in 2%, neurofibromatosis in 3%, and succinate dehydrogenase subunit B mutations in 2%.

In contrast, the most common mutation among the older patients with familial pheochromocytoma was MEN type 2a, in 15%. Dr. Barontini speculated that the higher incidence of VHL in the younger patients may account for the biochemical and clinical features—the noradrenergic profile—seen in this age group.

BETHESDA, MD. — Sustained, severe hypertension was among the clinical features of pheochromocytoma seen more frequently in patients under age 20, compared with adults, Dr. Marta Barontini said at an international symposium on pheochromocytoma sponsored by the National Institutes of Health.

Familial pheochromocytoma, mainly von Hippel-Lindau (VHL) disease, was also more common in the younger patients, “which may account for the noradrenergic profile” of their presenting symptoms, said Dr. Barontini of the center for endocrine research at the R. Gutiérrez Hospital for Children, Buenos Aires.

These findings were based on a review of 58 patients aged 4–20 (12 boys and 1 girl were younger than age 10; the rest were older), who represented 23% of the 255 pheochromocytoma patients studied at the endocrinology research center during a 40-year period. The purpose of the study was to establish clinical features of pheochromocytoma. Laboratory tests used to make the diagnosis, which was confirmed at the time of surgery, included urinary and plasma catecholamines (epinephrine, norepinephrine, and dopamine), as well as urinary levels of vanillylmandelic acid.

The differences between the clinical signs in the older patients at the center and those in the younger patients were “remarkable,” Dr. Barontini said. Sustained hypertension, headaches, and sweating were among the predominant characteristics seen in the younger patients: 93% had severe sustained hypertension, 7% had paroxysmal hypertension, and none was normotensive. Of the older patients, 69% had severe sustained hypertension, 26% had paroxysmal hypertension, and 5% were normotensive.

Other clinical signs often found in the younger patients were headaches in 95%, sweating in 90%, blurred vision in 80%, and encephalopathy in 65%. Palpitations, present in 35% of the younger patients, and weight loss, in 15%, were less common than they were in adults, she said.

Among the younger patients, 2% had normal norepinephrine levels, 55% had normal epinephrine levels, and 7% had normal urinary vanillylmandelic acid levels.

Of the patients under age 20, 34% had bilateral adrenal pheochromocytoma and 22% had extraadrenal pheochromocytoma. The incidence of both conditions was lower in the older patients.

Among the 58 younger patients, 7 (12%) had a malignant tumor, which was fatal in 4 patients: 1 patient died a few months after surgery and 3 died 8–18 years after surgery. The three patients still alive 5–21 years after surgery include one patient who has hypertension that is treated with four drugs. This patient also has high catecholamine levels and widespread bone metastases, but maintains a good quality of life, Dr. Barontini said.

Familial pheochromocytoma was identified in 36% of those younger than age 20, compared with 22% of the older patients. Genetic testing, which was performed in familial cases, found surprising differences.

VHL disease—an autosomal-dominant neoplasia disorder—had a higher prevalence in the younger population (28%), compared with that in the older patients. Multiple endocrine neoplasia (MEN) type 2a was identified in 2% of the younger patients, MEN type 2b in 2%, neurofibromatosis in 3%, and succinate dehydrogenase subunit B mutations in 2%.

In contrast, the most common mutation among the older patients with familial pheochromocytoma was MEN type 2a, in 15%. Dr. Barontini speculated that the higher incidence of VHL in the younger patients may account for the biochemical and clinical features—the noradrenergic profile—seen in this age group.

BETHESDA, MD. — Herpes simplex virus 1 has emerged as an important genital pathogen and is more likely than herpes simplex virus 2 to be the cause of primary genital herpes infections in young women, Sharon L. Hillier, Ph.D., said at a conference on vulvovaginal diseases.

Young, sexually active women are more susceptible to HSV-1 because most do not have protective antibodies to HSV-1 due to the dramatic drop in childhood HSV-1 infections, said Dr. Hillier, director, reproductive infectious disease research, Magee-Womens Hospital, Pittsburgh.

Among the major implications of this trend is the potential utility of the genital herpes vaccine that is being developed, since it targets only HSV-2, she pointed out.

Since current estimates of genital herpes from national seroprevalence studies include only HSV-2 infections, they “probably greatly underestimate the amount of genital herpes” in this country, Dr. Hillier said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

Studies documenting the emergence of HSV-1 as a cause of primary genital herpes infections date to 1990, when HSV-1 was found to have replaced HSV-2 as the most common cause of genital herpes in Scotland. Studies published in 2000 reported that HSV-1 was the cause of 85% of all primary genital HSV infections in Sweden and 70%-90% of all first episodes of genital herpes in women younger than 21 in Norway.

In the United States, a 2003 study found that the proportion of newly diagnosed genital herpes infections due to HSV-1 in a university student health service increased from 31% in 1993 to 78% in 2001.

In a recently published study, Dr. Hillier and her associates found that only 29% of a sample of college students at a University of Pittsburgh student health clinic had antibodies to HSV-1, making the majority susceptible to infection. The study enrolled 1,207 women aged 18–30 years at three different health clinics and found that the HSV-1 seroprevalence was 47% overall, but 60% at the primary care clinic and 51% at an STD clinic (Sex. Transm. Dis. 2005;32:84–9).

Their results indicated that age and number of sex partners was associated with HSV-1 seroprevalence: 38% of the women aged 18–20 years were positive for HSV-1 antibodies, increasing to 49% among those aged 21–25 years, and 64% among those aged 26–30 years. HSV-1 seroprevalence was 26% among those who previously had no sex partners, 41% among those who had one to four sex partners in their lifetime, and 53% among those who had five or more lifetime sex partners.

Follow-up of these women determined that cunnilingus and vaginal intercourse were risk factors for the acquisition of HSV-1 infections: Of the 516 HSV-1 seronegative women who returned for 1,833 visits, 29 acquired antibodies to HSV-1. That means that 6% of the women per year were acquiring herpes infections due to HSV-1 infection, said Dr. Hillier, also, professor of obstetrics, gynecology, and reproductive sciences, and of molecular genetics and biochemistry at the University of Pittsburgh.

When the researchers looked at sex practices, the acquisition rate for HSV-1 was highest among those who had receptive oral sex only, at 9.8 cases per 100 woman-years, compared with 1.2 per 100 woman-years among those who were not sexually active—a significant difference.

Among women having vaginal intercourse, the acquisition rate for HSV-1 was 6.8 cases per 100 woman-years, or 6.8% per year, she said. The HSV-2 acquisition rate was 5.7 cases per 100 woman-years among those reporting vaginal intercourse, but zero among those reporting receptive oral sex only.

Therefore, “women who report only oral sex are just as likely to acquire HSV-1 as women reporting vaginal sex,” Dr. Hillier concluded.

These data are similar to data reported from Scotland and Finland, indicating that oral sex increases the risk of HSV-1 “and has really changed the way we have begun to think about a lot of the women saying they have herpes,” she added.

BETHESDA, MD. — Herpes simplex virus 1 has emerged as an important genital pathogen and is more likely than herpes simplex virus 2 to be the cause of primary genital herpes infections in young women, Sharon L. Hillier, Ph.D., said at a conference on vulvovaginal diseases.

Young, sexually active women are more susceptible to HSV-1 because most do not have protective antibodies to HSV-1 due to the dramatic drop in childhood HSV-1 infections, said Dr. Hillier, director, reproductive infectious disease research, Magee-Womens Hospital, Pittsburgh.

Among the major implications of this trend is the potential utility of the genital herpes vaccine that is being developed, since it targets only HSV-2, she pointed out.

Since current estimates of genital herpes from national seroprevalence studies include only HSV-2 infections, they “probably greatly underestimate the amount of genital herpes” in this country, Dr. Hillier said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

Studies documenting the emergence of HSV-1 as a cause of primary genital herpes infections date to 1990, when HSV-1 was found to have replaced HSV-2 as the most common cause of genital herpes in Scotland. Studies published in 2000 reported that HSV-1 was the cause of 85% of all primary genital HSV infections in Sweden and 70%-90% of all first episodes of genital herpes in women younger than 21 in Norway.

In the United States, a 2003 study found that the proportion of newly diagnosed genital herpes infections due to HSV-1 in a university student health service increased from 31% in 1993 to 78% in 2001.

In a recently published study, Dr. Hillier and her associates found that only 29% of a sample of college students at a University of Pittsburgh student health clinic had antibodies to HSV-1, making the majority susceptible to infection. The study enrolled 1,207 women aged 18–30 years at three different health clinics and found that the HSV-1 seroprevalence was 47% overall, but 60% at the primary care clinic and 51% at an STD clinic (Sex. Transm. Dis. 2005;32:84–9).

Their results indicated that age and number of sex partners was associated with HSV-1 seroprevalence: 38% of the women aged 18–20 years were positive for HSV-1 antibodies, increasing to 49% among those aged 21–25 years, and 64% among those aged 26–30 years. HSV-1 seroprevalence was 26% among those who previously had no sex partners, 41% among those who had one to four sex partners in their lifetime, and 53% among those who had five or more lifetime sex partners.

Follow-up of these women determined that cunnilingus and vaginal intercourse were risk factors for the acquisition of HSV-1 infections: Of the 516 HSV-1 seronegative women who returned for 1,833 visits, 29 acquired antibodies to HSV-1. That means that 6% of the women per year were acquiring herpes infections due to HSV-1 infection, said Dr. Hillier, also, professor of obstetrics, gynecology, and reproductive sciences, and of molecular genetics and biochemistry at the University of Pittsburgh.

When the researchers looked at sex practices, the acquisition rate for HSV-1 was highest among those who had receptive oral sex only, at 9.8 cases per 100 woman-years, compared with 1.2 per 100 woman-years among those who were not sexually active—a significant difference.

Among women having vaginal intercourse, the acquisition rate for HSV-1 was 6.8 cases per 100 woman-years, or 6.8% per year, she said. The HSV-2 acquisition rate was 5.7 cases per 100 woman-years among those reporting vaginal intercourse, but zero among those reporting receptive oral sex only.

Therefore, “women who report only oral sex are just as likely to acquire HSV-1 as women reporting vaginal sex,” Dr. Hillier concluded.

These data are similar to data reported from Scotland and Finland, indicating that oral sex increases the risk of HSV-1 “and has really changed the way we have begun to think about a lot of the women saying they have herpes,” she added.

BETHESDA, MD. — Herpes simplex virus 1 has emerged as an important genital pathogen and is more likely than herpes simplex virus 2 to be the cause of primary genital herpes infections in young women, Sharon L. Hillier, Ph.D., said at a conference on vulvovaginal diseases.

Young, sexually active women are more susceptible to HSV-1 because most do not have protective antibodies to HSV-1 due to the dramatic drop in childhood HSV-1 infections, said Dr. Hillier, director, reproductive infectious disease research, Magee-Womens Hospital, Pittsburgh.

Among the major implications of this trend is the potential utility of the genital herpes vaccine that is being developed, since it targets only HSV-2, she pointed out.

Since current estimates of genital herpes from national seroprevalence studies include only HSV-2 infections, they “probably greatly underestimate the amount of genital herpes” in this country, Dr. Hillier said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

Studies documenting the emergence of HSV-1 as a cause of primary genital herpes infections date to 1990, when HSV-1 was found to have replaced HSV-2 as the most common cause of genital herpes in Scotland. Studies published in 2000 reported that HSV-1 was the cause of 85% of all primary genital HSV infections in Sweden and 70%-90% of all first episodes of genital herpes in women younger than 21 in Norway.

In the United States, a 2003 study found that the proportion of newly diagnosed genital herpes infections due to HSV-1 in a university student health service increased from 31% in 1993 to 78% in 2001.

In a recently published study, Dr. Hillier and her associates found that only 29% of a sample of college students at a University of Pittsburgh student health clinic had antibodies to HSV-1, making the majority susceptible to infection. The study enrolled 1,207 women aged 18–30 years at three different health clinics and found that the HSV-1 seroprevalence was 47% overall, but 60% at the primary care clinic and 51% at an STD clinic (Sex. Transm. Dis. 2005;32:84–9).

Their results indicated that age and number of sex partners was associated with HSV-1 seroprevalence: 38% of the women aged 18–20 years were positive for HSV-1 antibodies, increasing to 49% among those aged 21–25 years, and 64% among those aged 26–30 years. HSV-1 seroprevalence was 26% among those who previously had no sex partners, 41% among those who had one to four sex partners in their lifetime, and 53% among those who had five or more lifetime sex partners.

Follow-up of these women determined that cunnilingus and vaginal intercourse were risk factors for the acquisition of HSV-1 infections: Of the 516 HSV-1 seronegative women who returned for 1,833 visits, 29 acquired antibodies to HSV-1. That means that 6% of the women per year were acquiring herpes infections due to HSV-1 infection, said Dr. Hillier, also, professor of obstetrics, gynecology, and reproductive sciences, and of molecular genetics and biochemistry at the University of Pittsburgh.

When the researchers looked at sex practices, the acquisition rate for HSV-1 was highest among those who had receptive oral sex only, at 9.8 cases per 100 woman-years, compared with 1.2 per 100 woman-years among those who were not sexually active—a significant difference.

Among women having vaginal intercourse, the acquisition rate for HSV-1 was 6.8 cases per 100 woman-years, or 6.8% per year, she said. The HSV-2 acquisition rate was 5.7 cases per 100 woman-years among those reporting vaginal intercourse, but zero among those reporting receptive oral sex only.

Therefore, “women who report only oral sex are just as likely to acquire HSV-1 as women reporting vaginal sex,” Dr. Hillier concluded.

These data are similar to data reported from Scotland and Finland, indicating that oral sex increases the risk of HSV-1 “and has really changed the way we have begun to think about a lot of the women saying they have herpes,” she added.

A combination hormone therapy that contains drospirenone was approved in late September for treating moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause, the first such product to contain this particular progestin.

The approval came with certain warnings in the label related to the potential for hyperkalemia associated with the progestin component. The product—which contains 1 mg estradiol and 0.5 mg drospirenone (DRSP), a synthetic progestin and spironolactone analog with antimineralocorticoid activity—will be marketed by Berlex as Angeliq. The approved dose is one tablet daily.

The product will not be available until mid-2006, according to Berlex, which also manufactures Yasmin, the oral contraceptive that contains DRSP as its progestin component.

In addition to the standard contraindications and warnings that are included in the FDA-approved labels of all hormone therapy (HT) products, the Angeliq label includes a warning about the potential for hyperkalemia in high-risk patients, because DRSP has antialdosterone activity. The warning also notes that the product should not be used in women with renal or adrenal insufficiency, hepatic dysfunction, or other conditions that predispose people to hyperkalemia.

It should be used with caution in women on other medications that can increase potassium, including NSAIDs, potassium-sparing diuretics, ACE inhibitors, or angiotensin II receptor antagonists. The label says that checking serum potassium levels during the first treatment cycle in women at high risk should be considered.

FDA approval for the indication was based on a study showing that the estradiol component of Angeliq was bioequivalent to a currently marketed estradiol product (Estrace). In another study on the endometrial effects, there were no cases of endometrial hyperplasia among almost 200 patients who had received the product for up to 12 months.

For relief of symptoms, “it's another option that physicians can add to their armamentarium of the whole range of products now available,” Wulf H. Utian, M.D., executive director of the North American Menopause Society, said.

Because of its chemistry, Angeliq is less likely to cause fluid retention “at least in theory,” and potentially might be associated with fewer of what he calls the “nuisance symptoms” that some women experience with progestin, such as a bloated feeling; tender breasts; sleepiness; or a reduced sense of well-being or slightly depressed mood, Dr. Utian noted.

But because HT products are not directly compared in clinical trials and there are no published data on this issue, he said it was difficult to comment on the effect that the DRSP component might have on mitigating these types of side effects. Nevertheless, Dr. Utian said that he welcomed the availability of a new HT product as a positive development because it increased the number of treatment options for women, who react to different progestins in different ways.

What remains are major unresolved safety questions regarding the longer term use of progestins in general, when used with estrogen, Dr. Utian noted. Those questions are whether progestin administered with continuous estrogen treatment slightly increases the risk of breast cancer beyond 5 years of use, which has been observed in the WHI and other studies, and whether the progestin component may be responsible for the slight increase in coronary heart disease observed in the WHI and the Nurses' Health Study.

Dr. Utian, a gynecologist at the Cleveland Clinic Foundation, Cleveland, was not an investigator in Angeliq trials, but he is the director of a research institute that is currently conducting a study of this product.

A combination hormone therapy that contains drospirenone was approved in late September for treating moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause, the first such product to contain this particular progestin.

The approval came with certain warnings in the label related to the potential for hyperkalemia associated with the progestin component. The product—which contains 1 mg estradiol and 0.5 mg drospirenone (DRSP), a synthetic progestin and spironolactone analog with antimineralocorticoid activity—will be marketed by Berlex as Angeliq. The approved dose is one tablet daily.

The product will not be available until mid-2006, according to Berlex, which also manufactures Yasmin, the oral contraceptive that contains DRSP as its progestin component.

In addition to the standard contraindications and warnings that are included in the FDA-approved labels of all hormone therapy (HT) products, the Angeliq label includes a warning about the potential for hyperkalemia in high-risk patients, because DRSP has antialdosterone activity. The warning also notes that the product should not be used in women with renal or adrenal insufficiency, hepatic dysfunction, or other conditions that predispose people to hyperkalemia.

It should be used with caution in women on other medications that can increase potassium, including NSAIDs, potassium-sparing diuretics, ACE inhibitors, or angiotensin II receptor antagonists. The label says that checking serum potassium levels during the first treatment cycle in women at high risk should be considered.

FDA approval for the indication was based on a study showing that the estradiol component of Angeliq was bioequivalent to a currently marketed estradiol product (Estrace). In another study on the endometrial effects, there were no cases of endometrial hyperplasia among almost 200 patients who had received the product for up to 12 months.

For relief of symptoms, “it's another option that physicians can add to their armamentarium of the whole range of products now available,” Wulf H. Utian, M.D., executive director of the North American Menopause Society, said.

Because of its chemistry, Angeliq is less likely to cause fluid retention “at least in theory,” and potentially might be associated with fewer of what he calls the “nuisance symptoms” that some women experience with progestin, such as a bloated feeling; tender breasts; sleepiness; or a reduced sense of well-being or slightly depressed mood, Dr. Utian noted.

But because HT products are not directly compared in clinical trials and there are no published data on this issue, he said it was difficult to comment on the effect that the DRSP component might have on mitigating these types of side effects. Nevertheless, Dr. Utian said that he welcomed the availability of a new HT product as a positive development because it increased the number of treatment options for women, who react to different progestins in different ways.

What remains are major unresolved safety questions regarding the longer term use of progestins in general, when used with estrogen, Dr. Utian noted. Those questions are whether progestin administered with continuous estrogen treatment slightly increases the risk of breast cancer beyond 5 years of use, which has been observed in the WHI and other studies, and whether the progestin component may be responsible for the slight increase in coronary heart disease observed in the WHI and the Nurses' Health Study.

Dr. Utian, a gynecologist at the Cleveland Clinic Foundation, Cleveland, was not an investigator in Angeliq trials, but he is the director of a research institute that is currently conducting a study of this product.

A combination hormone therapy that contains drospirenone was approved in late September for treating moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause, the first such product to contain this particular progestin.

The approval came with certain warnings in the label related to the potential for hyperkalemia associated with the progestin component. The product—which contains 1 mg estradiol and 0.5 mg drospirenone (DRSP), a synthetic progestin and spironolactone analog with antimineralocorticoid activity—will be marketed by Berlex as Angeliq. The approved dose is one tablet daily.

The product will not be available until mid-2006, according to Berlex, which also manufactures Yasmin, the oral contraceptive that contains DRSP as its progestin component.

In addition to the standard contraindications and warnings that are included in the FDA-approved labels of all hormone therapy (HT) products, the Angeliq label includes a warning about the potential for hyperkalemia in high-risk patients, because DRSP has antialdosterone activity. The warning also notes that the product should not be used in women with renal or adrenal insufficiency, hepatic dysfunction, or other conditions that predispose people to hyperkalemia.

It should be used with caution in women on other medications that can increase potassium, including NSAIDs, potassium-sparing diuretics, ACE inhibitors, or angiotensin II receptor antagonists. The label says that checking serum potassium levels during the first treatment cycle in women at high risk should be considered.

FDA approval for the indication was based on a study showing that the estradiol component of Angeliq was bioequivalent to a currently marketed estradiol product (Estrace). In another study on the endometrial effects, there were no cases of endometrial hyperplasia among almost 200 patients who had received the product for up to 12 months.

For relief of symptoms, “it's another option that physicians can add to their armamentarium of the whole range of products now available,” Wulf H. Utian, M.D., executive director of the North American Menopause Society, said.

Because of its chemistry, Angeliq is less likely to cause fluid retention “at least in theory,” and potentially might be associated with fewer of what he calls the “nuisance symptoms” that some women experience with progestin, such as a bloated feeling; tender breasts; sleepiness; or a reduced sense of well-being or slightly depressed mood, Dr. Utian noted.

But because HT products are not directly compared in clinical trials and there are no published data on this issue, he said it was difficult to comment on the effect that the DRSP component might have on mitigating these types of side effects. Nevertheless, Dr. Utian said that he welcomed the availability of a new HT product as a positive development because it increased the number of treatment options for women, who react to different progestins in different ways.

What remains are major unresolved safety questions regarding the longer term use of progestins in general, when used with estrogen, Dr. Utian noted. Those questions are whether progestin administered with continuous estrogen treatment slightly increases the risk of breast cancer beyond 5 years of use, which has been observed in the WHI and other studies, and whether the progestin component may be responsible for the slight increase in coronary heart disease observed in the WHI and the Nurses' Health Study.

Dr. Utian, a gynecologist at the Cleveland Clinic Foundation, Cleveland, was not an investigator in Angeliq trials, but he is the director of a research institute that is currently conducting a study of this product.

ROCKVILLE, MD. — No new safety concerns were raised by a review of adverse events reported during a recent 1-year period in adolescents taking a combination oral contraceptive, according to Jean Wendy Temeck, M.D., of the Food and Drug Administration's division of pediatric drug development.

The FDA's review of adverse events reported for Ortho Tri-Cyclen and Ortho Tri-Cyclen Lo, which contain norgestimate and ethinyl estradiol, was conducted between December 2003 and January 2005, the year after the FDA granted marketing exclusivity to the drug. Exclusivity is granted to a drug when companies perform pediatric studies of the product in exchange for a 6-month extension on the drug's patent.

In this case, the manufacturer, Ortho-McNeil Pharmaceutical Inc., conducted a placebo-controlled study to determine whether the OC improved bone density in adolescent girls with anorexia nervosa. The study showed no differences from placebo in increases in hip and lumbar-spine bone mineral density after 1 year of treatment.

Dr. Temek reported the data at a meeting of the FDA's Pediatric Advisory Committee. The Best Pharmaceuticals for Children Act requires that the FDA's Office of Pediatric Therapeutics review postmarketing adverse event reports made to the FDA's MedWatch adverse event reporting system during the year after a drug receives exclusivity. These reports are then referred to the Pediatric Advisory Committee for a review.

The uses of Ortho Tri-Cyclen for females 16 years of age and younger include dysfunctional uterine bleeding and acne, she said. During the postexclusivity period (Dec. 18, 2003, through Jan. 18, 2005) there were 14 unduplicated pediatric adverse event reports associated with Ortho Tri-Cyclen, including 11 serious reports and 0 deaths.

The 14 reports included 12 cases in adolescent girls and 2 cases involving infants that had been exposed in utero. Adverse events that were reported more than once were headaches and metrorrhagia, events that are listed in the label of Ortho Tri-Cyclen, and convulsions, an adverse event that is not in the label.

There were four hospitalizations, which included the two in utero exposures. The other two hospitalizations were in a 16-year-old with benign intracranial hypertension, an increase in cerebrospinal fluid pressure, and a visual field defect; and in a 14-year-old who had cerebral thrombosis and headache. These two patients were also on isotretinoin.

A third patient who was also on isotretinoin, as well as prednisone, was reported to have depression, dizziness, and headache, which are unlabeled events for the OC; other symptoms included decreased interest, insomnia, and panic attack. (The labels for isotretinoin and prednisone include the risk of increased intracranial pressure, depression, insomnia, emotional instability, dizziness, and headache, Dr. Temeck noted.)

Of the two infants exposed in utero, one was in a breech presentation and born prematurely, and the baby's mother also had taken penicillin, betamethasone, and alprazolam while pregnant. The second exposed infant had cerebral artery occlusion, convulsion, apnea, and developmental delay.

There were three adolescents who reported visual adverse events, which are not mentioned in the Ortho Tri-Cyclen label: a 14-year-old also on oxcarbazepine who was reported to have papilledema and cluster headache; a 16-year-old also on doxycycline and tretinoin, who had scotoma, blurred vision, headache, and influenzalike illness; and a 16-year-old also on isotretinoin and prednisone, who had a visual-field defect, in addition to benign intracranial hypertension and increased CSF pressure. (The label for Ortho Tri-Cyclen warns of retinal thrombosis.)

The other two serious adverse events were in one 14-year-old who developed hypertension and another 14-year-old who had dysarthria and hypoesthesia—two events not on the label. Convulsions also were reported in a 15-year-old who had a history of intermittent seizures.

Despite the reports of some serious adverse events reported during this period, “no pattern of new safety concerns” was identified, Dr. Temeck said. Based on the presentation, the advisory panel agreed with the FDA that monitoring of adverse events for these OCs could be switched to regular monitoring.

Health care professionals and consumers can report drug- or device-related adverse events to MedWatch by calling 800-332-1088, sending a fax to 800-332-0178, writing to MedWatch, Food and Drug Administration, 5600 Fishers Ln., Rockville, MD 20857-9787; or visiting www.fda.gov/medwatch

ROCKVILLE, MD. — No new safety concerns were raised by a review of adverse events reported during a recent 1-year period in adolescents taking a combination oral contraceptive, according to Jean Wendy Temeck, M.D., of the Food and Drug Administration's division of pediatric drug development.

The FDA's review of adverse events reported for Ortho Tri-Cyclen and Ortho Tri-Cyclen Lo, which contain norgestimate and ethinyl estradiol, was conducted between December 2003 and January 2005, the year after the FDA granted marketing exclusivity to the drug. Exclusivity is granted to a drug when companies perform pediatric studies of the product in exchange for a 6-month extension on the drug's patent.

In this case, the manufacturer, Ortho-McNeil Pharmaceutical Inc., conducted a placebo-controlled study to determine whether the OC improved bone density in adolescent girls with anorexia nervosa. The study showed no differences from placebo in increases in hip and lumbar-spine bone mineral density after 1 year of treatment.

Dr. Temek reported the data at a meeting of the FDA's Pediatric Advisory Committee. The Best Pharmaceuticals for Children Act requires that the FDA's Office of Pediatric Therapeutics review postmarketing adverse event reports made to the FDA's MedWatch adverse event reporting system during the year after a drug receives exclusivity. These reports are then referred to the Pediatric Advisory Committee for a review.

The uses of Ortho Tri-Cyclen for females 16 years of age and younger include dysfunctional uterine bleeding and acne, she said. During the postexclusivity period (Dec. 18, 2003, through Jan. 18, 2005) there were 14 unduplicated pediatric adverse event reports associated with Ortho Tri-Cyclen, including 11 serious reports and 0 deaths.

The 14 reports included 12 cases in adolescent girls and 2 cases involving infants that had been exposed in utero. Adverse events that were reported more than once were headaches and metrorrhagia, events that are listed in the label of Ortho Tri-Cyclen, and convulsions, an adverse event that is not in the label.

There were four hospitalizations, which included the two in utero exposures. The other two hospitalizations were in a 16-year-old with benign intracranial hypertension, an increase in cerebrospinal fluid pressure, and a visual field defect; and in a 14-year-old who had cerebral thrombosis and headache. These two patients were also on isotretinoin.

A third patient who was also on isotretinoin, as well as prednisone, was reported to have depression, dizziness, and headache, which are unlabeled events for the OC; other symptoms included decreased interest, insomnia, and panic attack. (The labels for isotretinoin and prednisone include the risk of increased intracranial pressure, depression, insomnia, emotional instability, dizziness, and headache, Dr. Temeck noted.)

Of the two infants exposed in utero, one was in a breech presentation and born prematurely, and the baby's mother also had taken penicillin, betamethasone, and alprazolam while pregnant. The second exposed infant had cerebral artery occlusion, convulsion, apnea, and developmental delay.

There were three adolescents who reported visual adverse events, which are not mentioned in the Ortho Tri-Cyclen label: a 14-year-old also on oxcarbazepine who was reported to have papilledema and cluster headache; a 16-year-old also on doxycycline and tretinoin, who had scotoma, blurred vision, headache, and influenzalike illness; and a 16-year-old also on isotretinoin and prednisone, who had a visual-field defect, in addition to benign intracranial hypertension and increased CSF pressure. (The label for Ortho Tri-Cyclen warns of retinal thrombosis.)

The other two serious adverse events were in one 14-year-old who developed hypertension and another 14-year-old who had dysarthria and hypoesthesia—two events not on the label. Convulsions also were reported in a 15-year-old who had a history of intermittent seizures.

Despite the reports of some serious adverse events reported during this period, “no pattern of new safety concerns” was identified, Dr. Temeck said. Based on the presentation, the advisory panel agreed with the FDA that monitoring of adverse events for these OCs could be switched to regular monitoring.

Health care professionals and consumers can report drug- or device-related adverse events to MedWatch by calling 800-332-1088, sending a fax to 800-332-0178, writing to MedWatch, Food and Drug Administration, 5600 Fishers Ln., Rockville, MD 20857-9787; or visiting www.fda.gov/medwatch

ROCKVILLE, MD. — No new safety concerns were raised by a review of adverse events reported during a recent 1-year period in adolescents taking a combination oral contraceptive, according to Jean Wendy Temeck, M.D., of the Food and Drug Administration's division of pediatric drug development.

The FDA's review of adverse events reported for Ortho Tri-Cyclen and Ortho Tri-Cyclen Lo, which contain norgestimate and ethinyl estradiol, was conducted between December 2003 and January 2005, the year after the FDA granted marketing exclusivity to the drug. Exclusivity is granted to a drug when companies perform pediatric studies of the product in exchange for a 6-month extension on the drug's patent.

In this case, the manufacturer, Ortho-McNeil Pharmaceutical Inc., conducted a placebo-controlled study to determine whether the OC improved bone density in adolescent girls with anorexia nervosa. The study showed no differences from placebo in increases in hip and lumbar-spine bone mineral density after 1 year of treatment.

Dr. Temek reported the data at a meeting of the FDA's Pediatric Advisory Committee. The Best Pharmaceuticals for Children Act requires that the FDA's Office of Pediatric Therapeutics review postmarketing adverse event reports made to the FDA's MedWatch adverse event reporting system during the year after a drug receives exclusivity. These reports are then referred to the Pediatric Advisory Committee for a review.

The uses of Ortho Tri-Cyclen for females 16 years of age and younger include dysfunctional uterine bleeding and acne, she said. During the postexclusivity period (Dec. 18, 2003, through Jan. 18, 2005) there were 14 unduplicated pediatric adverse event reports associated with Ortho Tri-Cyclen, including 11 serious reports and 0 deaths.

The 14 reports included 12 cases in adolescent girls and 2 cases involving infants that had been exposed in utero. Adverse events that were reported more than once were headaches and metrorrhagia, events that are listed in the label of Ortho Tri-Cyclen, and convulsions, an adverse event that is not in the label.

There were four hospitalizations, which included the two in utero exposures. The other two hospitalizations were in a 16-year-old with benign intracranial hypertension, an increase in cerebrospinal fluid pressure, and a visual field defect; and in a 14-year-old who had cerebral thrombosis and headache. These two patients were also on isotretinoin.

A third patient who was also on isotretinoin, as well as prednisone, was reported to have depression, dizziness, and headache, which are unlabeled events for the OC; other symptoms included decreased interest, insomnia, and panic attack. (The labels for isotretinoin and prednisone include the risk of increased intracranial pressure, depression, insomnia, emotional instability, dizziness, and headache, Dr. Temeck noted.)

Of the two infants exposed in utero, one was in a breech presentation and born prematurely, and the baby's mother also had taken penicillin, betamethasone, and alprazolam while pregnant. The second exposed infant had cerebral artery occlusion, convulsion, apnea, and developmental delay.

There were three adolescents who reported visual adverse events, which are not mentioned in the Ortho Tri-Cyclen label: a 14-year-old also on oxcarbazepine who was reported to have papilledema and cluster headache; a 16-year-old also on doxycycline and tretinoin, who had scotoma, blurred vision, headache, and influenzalike illness; and a 16-year-old also on isotretinoin and prednisone, who had a visual-field defect, in addition to benign intracranial hypertension and increased CSF pressure. (The label for Ortho Tri-Cyclen warns of retinal thrombosis.)

The other two serious adverse events were in one 14-year-old who developed hypertension and another 14-year-old who had dysarthria and hypoesthesia—two events not on the label. Convulsions also were reported in a 15-year-old who had a history of intermittent seizures.

Despite the reports of some serious adverse events reported during this period, “no pattern of new safety concerns” was identified, Dr. Temeck said. Based on the presentation, the advisory panel agreed with the FDA that monitoring of adverse events for these OCs could be switched to regular monitoring.

Health care professionals and consumers can report drug- or device-related adverse events to MedWatch by calling 800-332-1088, sending a fax to 800-332-0178, writing to MedWatch, Food and Drug Administration, 5600 Fishers Ln., Rockville, MD 20857-9787; or visiting www.fda.gov/medwatch

ROCKVILLE, MD. — No new safety concerns were raised in a review of pediatric adverse event reports for the muscarinic receptor antagonist tolterodine, according to the Food and Drug Administration.

Tolterodine is marketed as Detrol and Detrol LA (the extended-release formulation). Among the drug's indications is treatment of overactive bladder in both neurologically impaired and neurologically intact children.

Dr. Larry Grylack, a medical officer in the FDA's division of pediatric drug development, Rockville, Md., presented data before the FDA's Pediatric Advisory Committee from pediatric exclusivity studies in neurologically impaired and intact children with overactive bladder, as well as data from other studies by Pfizer.

The three 12-week, open-label studies of neurologically impaired children enrolled 34 patients aged 1 month to 15 years, who received different doses of Detrol immediate release syrup or Detrol LA capsules. The urodynamic data were inconsistent within and across trials, and there was a “lack of dose response trends” across studies, Dr. Grylack told the panel. The two phase III studies of neurologically intact patients with overactive bladder, aged 5–10, found no significant differences in the number of weekly incontinence episodes during waking hours in the 486 children on Detrol LA (2 mg/day), compared with the 224 on placebo.

In these and the other Pfizer studies, of 917 pediatric patients taking tolterodine, 20 patients reported 24 serious adverse events, including four lower urinary tract infections (UTIs) and three cases of pyelonephritis. There were no deaths. There also were reports of aggressive and/or abnormal behavior in 18 patients, which were called nonserious adverse events, Dr. Grylack said. The Detrol LA label already includes information on the excess number of UTIs and episodes of abnormal behavior in patients treated with tolterodine, compared with those on placebo, he noted.

The adverse event reporting system database entries from 1998, when Detrol was approved, through February 2005 included 29 unduplicated pediatric adverse event reports (25 for Detrol and 4 for Detrol LA). Nine were anticholinergic events, including lethargy, urine retention, constipation, dry mouth, and blurred vision, as listed on the labels. But events also included overheating, confusion, and flushing.

There also were eight reports of CNS stimulation: These included reports of aggression and hyperactivity, which are not listed in the Detrol label but are on the Detrol LA label; and irritability and insomnia, which are not on either label. There were two reports of UTIs, three of medication errors, and five classified as “other.”

ROCKVILLE, MD. — No new safety concerns were raised in a review of pediatric adverse event reports for the muscarinic receptor antagonist tolterodine, according to the Food and Drug Administration.

Tolterodine is marketed as Detrol and Detrol LA (the extended-release formulation). Among the drug's indications is treatment of overactive bladder in both neurologically impaired and neurologically intact children.

Dr. Larry Grylack, a medical officer in the FDA's division of pediatric drug development, Rockville, Md., presented data before the FDA's Pediatric Advisory Committee from pediatric exclusivity studies in neurologically impaired and intact children with overactive bladder, as well as data from other studies by Pfizer.

The three 12-week, open-label studies of neurologically impaired children enrolled 34 patients aged 1 month to 15 years, who received different doses of Detrol immediate release syrup or Detrol LA capsules. The urodynamic data were inconsistent within and across trials, and there was a “lack of dose response trends” across studies, Dr. Grylack told the panel. The two phase III studies of neurologically intact patients with overactive bladder, aged 5–10, found no significant differences in the number of weekly incontinence episodes during waking hours in the 486 children on Detrol LA (2 mg/day), compared with the 224 on placebo.

In these and the other Pfizer studies, of 917 pediatric patients taking tolterodine, 20 patients reported 24 serious adverse events, including four lower urinary tract infections (UTIs) and three cases of pyelonephritis. There were no deaths. There also were reports of aggressive and/or abnormal behavior in 18 patients, which were called nonserious adverse events, Dr. Grylack said. The Detrol LA label already includes information on the excess number of UTIs and episodes of abnormal behavior in patients treated with tolterodine, compared with those on placebo, he noted.

The adverse event reporting system database entries from 1998, when Detrol was approved, through February 2005 included 29 unduplicated pediatric adverse event reports (25 for Detrol and 4 for Detrol LA). Nine were anticholinergic events, including lethargy, urine retention, constipation, dry mouth, and blurred vision, as listed on the labels. But events also included overheating, confusion, and flushing.

There also were eight reports of CNS stimulation: These included reports of aggression and hyperactivity, which are not listed in the Detrol label but are on the Detrol LA label; and irritability and insomnia, which are not on either label. There were two reports of UTIs, three of medication errors, and five classified as “other.”

ROCKVILLE, MD. — No new safety concerns were raised in a review of pediatric adverse event reports for the muscarinic receptor antagonist tolterodine, according to the Food and Drug Administration.

Tolterodine is marketed as Detrol and Detrol LA (the extended-release formulation). Among the drug's indications is treatment of overactive bladder in both neurologically impaired and neurologically intact children.

Dr. Larry Grylack, a medical officer in the FDA's division of pediatric drug development, Rockville, Md., presented data before the FDA's Pediatric Advisory Committee from pediatric exclusivity studies in neurologically impaired and intact children with overactive bladder, as well as data from other studies by Pfizer.

The three 12-week, open-label studies of neurologically impaired children enrolled 34 patients aged 1 month to 15 years, who received different doses of Detrol immediate release syrup or Detrol LA capsules. The urodynamic data were inconsistent within and across trials, and there was a “lack of dose response trends” across studies, Dr. Grylack told the panel. The two phase III studies of neurologically intact patients with overactive bladder, aged 5–10, found no significant differences in the number of weekly incontinence episodes during waking hours in the 486 children on Detrol LA (2 mg/day), compared with the 224 on placebo.

In these and the other Pfizer studies, of 917 pediatric patients taking tolterodine, 20 patients reported 24 serious adverse events, including four lower urinary tract infections (UTIs) and three cases of pyelonephritis. There were no deaths. There also were reports of aggressive and/or abnormal behavior in 18 patients, which were called nonserious adverse events, Dr. Grylack said. The Detrol LA label already includes information on the excess number of UTIs and episodes of abnormal behavior in patients treated with tolterodine, compared with those on placebo, he noted.

The adverse event reporting system database entries from 1998, when Detrol was approved, through February 2005 included 29 unduplicated pediatric adverse event reports (25 for Detrol and 4 for Detrol LA). Nine were anticholinergic events, including lethargy, urine retention, constipation, dry mouth, and blurred vision, as listed on the labels. But events also included overheating, confusion, and flushing.

There also were eight reports of CNS stimulation: These included reports of aggression and hyperactivity, which are not listed in the Detrol label but are on the Detrol LA label; and irritability and insomnia, which are not on either label. There were two reports of UTIs, three of medication errors, and five classified as “other.”