Elizabeth Mechcatie

Implanon, the first long-term implantable contraceptive to win FDA approval and become available in the United States since 2000 when Wyeth stopped marketing Norplant, may not be effective in women taking antiepileptic drugs, said Dr. Andrew M. Kaunitz.

A single-rod contraceptive implant that is about the size of a matchstick, Implanon is highly effective for up to 3 years in women who do not take antiseizure medication.

In an interview, Dr. Kaunitz, professor and assistant chairman of the department of obstetrics and gynecology at the University of Florida Health Science Center, Jacksonville, said that because their contraceptive efficacy is associated with low serum progestin levels, “contraceptive implants and progestin-only OCs do not represent optimal contraceptives for women who take (or will soon initiate) anticonvulsants or other concomitant medications, which induce hepatic enzymes.” Dr. Kaunitz's department has conducted clinical trials for Organon.

The label includes a warning and precautions about Implanon and antiepileptic interactions and other drugs that are potent inducers of hepatic enzymes, because coadministration may substantially lower etono- gestrel levels and reduce the effectiveness of the contraceptive. The drugs include phenytoin, carbamazepine, felbamate, topiramate, and oxcarbazepine.

In trials, bleeding irregularities were frequent and were the most common reason for choosing to discontinue the contraceptive.

Implants and progestin-only OCs could induce hepatic enzymes in those taking anticonvulsants. DR. KAUNITZ

Implanon, the first long-term implantable contraceptive to win FDA approval and become available in the United States since 2000 when Wyeth stopped marketing Norplant, may not be effective in women taking antiepileptic drugs, said Dr. Andrew M. Kaunitz.

A single-rod contraceptive implant that is about the size of a matchstick, Implanon is highly effective for up to 3 years in women who do not take antiseizure medication.

In an interview, Dr. Kaunitz, professor and assistant chairman of the department of obstetrics and gynecology at the University of Florida Health Science Center, Jacksonville, said that because their contraceptive efficacy is associated with low serum progestin levels, “contraceptive implants and progestin-only OCs do not represent optimal contraceptives for women who take (or will soon initiate) anticonvulsants or other concomitant medications, which induce hepatic enzymes.” Dr. Kaunitz's department has conducted clinical trials for Organon.

The label includes a warning and precautions about Implanon and antiepileptic interactions and other drugs that are potent inducers of hepatic enzymes, because coadministration may substantially lower etono- gestrel levels and reduce the effectiveness of the contraceptive. The drugs include phenytoin, carbamazepine, felbamate, topiramate, and oxcarbazepine.

In trials, bleeding irregularities were frequent and were the most common reason for choosing to discontinue the contraceptive.

Implants and progestin-only OCs could induce hepatic enzymes in those taking anticonvulsants. DR. KAUNITZ

Implanon, the first long-term implantable contraceptive to win FDA approval and become available in the United States since 2000 when Wyeth stopped marketing Norplant, may not be effective in women taking antiepileptic drugs, said Dr. Andrew M. Kaunitz.

A single-rod contraceptive implant that is about the size of a matchstick, Implanon is highly effective for up to 3 years in women who do not take antiseizure medication.

In an interview, Dr. Kaunitz, professor and assistant chairman of the department of obstetrics and gynecology at the University of Florida Health Science Center, Jacksonville, said that because their contraceptive efficacy is associated with low serum progestin levels, “contraceptive implants and progestin-only OCs do not represent optimal contraceptives for women who take (or will soon initiate) anticonvulsants or other concomitant medications, which induce hepatic enzymes.” Dr. Kaunitz's department has conducted clinical trials for Organon.

The label includes a warning and precautions about Implanon and antiepileptic interactions and other drugs that are potent inducers of hepatic enzymes, because coadministration may substantially lower etono- gestrel levels and reduce the effectiveness of the contraceptive. The drugs include phenytoin, carbamazepine, felbamate, topiramate, and oxcarbazepine.

In trials, bleeding irregularities were frequent and were the most common reason for choosing to discontinue the contraceptive.

Implants and progestin-only OCs could induce hepatic enzymes in those taking anticonvulsants. DR. KAUNITZ

ROCKVILLE, MD. — The postmarketing safety program in place for the pulmonary arterial hypertension drug bosentan resulted in a label change that describes rare cases of cirrhosis in closely monitored patients after prolonged treatment with the drug and reemphasizes the importance of monthly liver function testing in patients.

The changes in the label were announced in a “Dear Healthcare Professional” letter dated March 1, from bosentan manufacturer Actelion Pharmaceuticals US Inc., which describes a case of a female patient who was treated with the recommended dose of bosentan for 21 months. During the second year of treatment, the patient developed worsening liver function tests and eventually, developed liver failure but improved months after stopping the drug.

Bosentan was approved in 2001 for PAH (World Health Organization group I) patients, with WHO Class I or IV symptoms. A required postmarketing surveillance program was in place to monitor patients for liver damage and pregnancies as long as they are on the drug, which can cause liver damage and is teratogenic. Bosentan, an endothelin receptor antagonist marketed as Tracleer by Actelion, was approved in 2001, based on two placebo-controlled studies of 245 patients with PAH, representing 59 patient-years of treatment. The studies found that treatment resulted in improvements in exercise tolerance and delayed clinical worsening. The drug was associated with increased liver aminotransferase levels in 11% of treated subjects, which was reversible when the drug was discontinued.

Speaking at a meeting sponsored by the International Society for Pharmacoepidemiology, Dr. Eleanor Segal, vice president and head, global drug safety for Actelion Pharmaceuticals, South San Francisco, Calif., said that the hepatic risks of the drug were known, because a higher dose of the drug had been developed as an antihypertensive treatment, but was dropped because of the hepatic risks. The drug's benefits were considered higher than its risks for people with PAH, a life-threatening orphan disease, she said. (Bosentan was the first oral treatment approved for treating PAH; other treatments have since been approved.)

The postmarketing risk management program for bosentan in the United States, the Tracleer Access Program (TAP), tracks and reports to the Food and Drug Administration all adverse events related to liver injury in treated patients and the outcomes; prescribing physicians are required to enroll patients in the program, which relies on controlled distribution and patient contact to ensure monthly tests for liver enzyme changes are done.

Specifically, the distributors contact every patient on the drug before shipping their monthly supply, asking them if they have had their monthly liver function tests (LFTs), and, for female patients who are of childbearing potential, if they have had their monthly pregnancy test. If they have not, or can't remember if they were tested, the patients don't get the drug and the distributor contacts the prescribing physician.

The company is also required by the FDA to initiate a safety report for any pregnancy, any elevation in liver enzymes greater than eight times the upper limit of normal, any elevation of liver enzyme that occurred with bilirubin elevation at least two times the ULN, and any clinical liver injury associated with hospitalization, liver transplant, or death. A black box warning about the risk of liver damage and pregnancy is included in the label.

As of April, 31,000 patients had been exposed to the drug, with 21,000 patient-years of experience, Dr. Segal said.

The letter issued by Actelion describes the report of the patient whose LFTs remained near baseline during the first year of treatment on the recommended dosage of bosentan. At about 1 year, her (alanine aminotransferase (ALT) level gradually increased to 2–4 times her baseline level, which remained within normal limits, but 9 months later, she had marked elevations in aminotransferase and bilirubin levels and the drug was stopped. Aspartate aminotransferase (AST) and ALT levels remained high and bilirubin continued to increase. She developed liver failure and biopsy-confirmed cirrhosis, according to the letter, which said that the contribution of bosentan to the development of liver failure “could not be ruled out.”

Eventually, the letter said, the liver failure abated, and LFTs recovered about 7 months after stopping the drug. The patient had had PAH since she was a child, had many comorbidities, and was on various drug treatments when she started bosentan.

“This case underscores the need to continue monthly monitoring for the duration of Tracleer treatment,” the letter says.

ROCKVILLE, MD. — The postmarketing safety program in place for the pulmonary arterial hypertension drug bosentan resulted in a label change that describes rare cases of cirrhosis in closely monitored patients after prolonged treatment with the drug and reemphasizes the importance of monthly liver function testing in patients.

The changes in the label were announced in a “Dear Healthcare Professional” letter dated March 1, from bosentan manufacturer Actelion Pharmaceuticals US Inc., which describes a case of a female patient who was treated with the recommended dose of bosentan for 21 months. During the second year of treatment, the patient developed worsening liver function tests and eventually, developed liver failure but improved months after stopping the drug.

Bosentan was approved in 2001 for PAH (World Health Organization group I) patients, with WHO Class I or IV symptoms. A required postmarketing surveillance program was in place to monitor patients for liver damage and pregnancies as long as they are on the drug, which can cause liver damage and is teratogenic. Bosentan, an endothelin receptor antagonist marketed as Tracleer by Actelion, was approved in 2001, based on two placebo-controlled studies of 245 patients with PAH, representing 59 patient-years of treatment. The studies found that treatment resulted in improvements in exercise tolerance and delayed clinical worsening. The drug was associated with increased liver aminotransferase levels in 11% of treated subjects, which was reversible when the drug was discontinued.

Speaking at a meeting sponsored by the International Society for Pharmacoepidemiology, Dr. Eleanor Segal, vice president and head, global drug safety for Actelion Pharmaceuticals, South San Francisco, Calif., said that the hepatic risks of the drug were known, because a higher dose of the drug had been developed as an antihypertensive treatment, but was dropped because of the hepatic risks. The drug's benefits were considered higher than its risks for people with PAH, a life-threatening orphan disease, she said. (Bosentan was the first oral treatment approved for treating PAH; other treatments have since been approved.)

The postmarketing risk management program for bosentan in the United States, the Tracleer Access Program (TAP), tracks and reports to the Food and Drug Administration all adverse events related to liver injury in treated patients and the outcomes; prescribing physicians are required to enroll patients in the program, which relies on controlled distribution and patient contact to ensure monthly tests for liver enzyme changes are done.

Specifically, the distributors contact every patient on the drug before shipping their monthly supply, asking them if they have had their monthly liver function tests (LFTs), and, for female patients who are of childbearing potential, if they have had their monthly pregnancy test. If they have not, or can't remember if they were tested, the patients don't get the drug and the distributor contacts the prescribing physician.

The company is also required by the FDA to initiate a safety report for any pregnancy, any elevation in liver enzymes greater than eight times the upper limit of normal, any elevation of liver enzyme that occurred with bilirubin elevation at least two times the ULN, and any clinical liver injury associated with hospitalization, liver transplant, or death. A black box warning about the risk of liver damage and pregnancy is included in the label.

As of April, 31,000 patients had been exposed to the drug, with 21,000 patient-years of experience, Dr. Segal said.

The letter issued by Actelion describes the report of the patient whose LFTs remained near baseline during the first year of treatment on the recommended dosage of bosentan. At about 1 year, her (alanine aminotransferase (ALT) level gradually increased to 2–4 times her baseline level, which remained within normal limits, but 9 months later, she had marked elevations in aminotransferase and bilirubin levels and the drug was stopped. Aspartate aminotransferase (AST) and ALT levels remained high and bilirubin continued to increase. She developed liver failure and biopsy-confirmed cirrhosis, according to the letter, which said that the contribution of bosentan to the development of liver failure “could not be ruled out.”

Eventually, the letter said, the liver failure abated, and LFTs recovered about 7 months after stopping the drug. The patient had had PAH since she was a child, had many comorbidities, and was on various drug treatments when she started bosentan.

“This case underscores the need to continue monthly monitoring for the duration of Tracleer treatment,” the letter says.

ROCKVILLE, MD. — The postmarketing safety program in place for the pulmonary arterial hypertension drug bosentan resulted in a label change that describes rare cases of cirrhosis in closely monitored patients after prolonged treatment with the drug and reemphasizes the importance of monthly liver function testing in patients.

The changes in the label were announced in a “Dear Healthcare Professional” letter dated March 1, from bosentan manufacturer Actelion Pharmaceuticals US Inc., which describes a case of a female patient who was treated with the recommended dose of bosentan for 21 months. During the second year of treatment, the patient developed worsening liver function tests and eventually, developed liver failure but improved months after stopping the drug.

Bosentan was approved in 2001 for PAH (World Health Organization group I) patients, with WHO Class I or IV symptoms. A required postmarketing surveillance program was in place to monitor patients for liver damage and pregnancies as long as they are on the drug, which can cause liver damage and is teratogenic. Bosentan, an endothelin receptor antagonist marketed as Tracleer by Actelion, was approved in 2001, based on two placebo-controlled studies of 245 patients with PAH, representing 59 patient-years of treatment. The studies found that treatment resulted in improvements in exercise tolerance and delayed clinical worsening. The drug was associated with increased liver aminotransferase levels in 11% of treated subjects, which was reversible when the drug was discontinued.

Speaking at a meeting sponsored by the International Society for Pharmacoepidemiology, Dr. Eleanor Segal, vice president and head, global drug safety for Actelion Pharmaceuticals, South San Francisco, Calif., said that the hepatic risks of the drug were known, because a higher dose of the drug had been developed as an antihypertensive treatment, but was dropped because of the hepatic risks. The drug's benefits were considered higher than its risks for people with PAH, a life-threatening orphan disease, she said. (Bosentan was the first oral treatment approved for treating PAH; other treatments have since been approved.)

The postmarketing risk management program for bosentan in the United States, the Tracleer Access Program (TAP), tracks and reports to the Food and Drug Administration all adverse events related to liver injury in treated patients and the outcomes; prescribing physicians are required to enroll patients in the program, which relies on controlled distribution and patient contact to ensure monthly tests for liver enzyme changes are done.

Specifically, the distributors contact every patient on the drug before shipping their monthly supply, asking them if they have had their monthly liver function tests (LFTs), and, for female patients who are of childbearing potential, if they have had their monthly pregnancy test. If they have not, or can't remember if they were tested, the patients don't get the drug and the distributor contacts the prescribing physician.

The company is also required by the FDA to initiate a safety report for any pregnancy, any elevation in liver enzymes greater than eight times the upper limit of normal, any elevation of liver enzyme that occurred with bilirubin elevation at least two times the ULN, and any clinical liver injury associated with hospitalization, liver transplant, or death. A black box warning about the risk of liver damage and pregnancy is included in the label.

As of April, 31,000 patients had been exposed to the drug, with 21,000 patient-years of experience, Dr. Segal said.

The letter issued by Actelion describes the report of the patient whose LFTs remained near baseline during the first year of treatment on the recommended dosage of bosentan. At about 1 year, her (alanine aminotransferase (ALT) level gradually increased to 2–4 times her baseline level, which remained within normal limits, but 9 months later, she had marked elevations in aminotransferase and bilirubin levels and the drug was stopped. Aspartate aminotransferase (AST) and ALT levels remained high and bilirubin continued to increase. She developed liver failure and biopsy-confirmed cirrhosis, according to the letter, which said that the contribution of bosentan to the development of liver failure “could not be ruled out.”

Eventually, the letter said, the liver failure abated, and LFTs recovered about 7 months after stopping the drug. The patient had had PAH since she was a child, had many comorbidities, and was on various drug treatments when she started bosentan.

“This case underscores the need to continue monthly monitoring for the duration of Tracleer treatment,” the letter says.

The recent approval of an irreversible monoamine oxidase inhibitor for treating Parkinson's disease includes an indication for patients with early disease as well as for those with more advanced disease who are already on levodopa.

Last month, the Food and Drug Administration approved rasagiline for treating the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. Rasagiline, which will be marketed under the trade name Azilect by the Israel-based company Teva Pharmaceutical Industries Ltd., will be available sometime in July, according to the company. The recommended monotherapy dose is 1 mg once daily; for adjunctive therapy, the recommended starting dose is 0.5 mg once daily, increasing to 1 mg once daily if the clinical response is not adequate.

The approval comes with a warning about the need to restrict dietary tyramine and amines contained in medications in order to avoid the risk of a hypertensive crisis, as well as a precaution about monitoring patients for melanoma.

Rasagiline–a new molecular entity that was approved in Europe and Israel last year–inhibits monoamine oxidase type B (MAO-B). Whether it is selective for and inhibits only MAO-B and not MAO-A in humans has not been adequately studied yet, according to the drug's label. The label also states that its precise mechanism of action is unknown, but is believed to be “related to inhibition of MAO-B,” which results in increased extracellular levels of dopamine in the striatum.

FDA approval was based on three 18- to 26-week, randomized, placebo-controlled studies. In the monotherapy study of 404 patients with early Parkinson's disease, those treated with rasagiline experienced significantly less worsening in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) at 6 months, when compared with those on placebo. The two other studies assessed the drug in more than 1,100 patients with more advanced disease. Study participants had had Parkinson's for an average of 9 years, were on chronic levodopa therapy, and were having motor fluctuations. Compared with those on placebo, subjects who received rasagiline had significantly less daily “off” time when their function and mobility were relatively poor.

Dr. Irene Litvan, the Raymond Lee Lebby Professor of Parkinson Disease Research at the University of Louisville (Ky.), described the approval as “great news” because the drug can be used both as monotherapy early in the course of the disease as well as an adjunct agent later in the disease's progression. In addition, the drug causes few side effects, is taken once a day, and does not need to be titrated.

Rasagiline is “an important new treatment … that can not only improve some of the symptoms of Parkinson's disease, but has the potential to slow the progression of the disease,” she said in an interview. This potential neuroprotective effect of the drug is the most exciting aspect of the approval and is what many patients have been waiting for, she added, noting that animal and in vitro data and some clinical evidence suggest rasagiline has some neuroprotective benefits.

Teva is currently recruiting patients with early idiopathic Parkinson's disease for a multinational trial to evaluate the effects of rasagiline on slowing the progression of the disease.

Even before approval, the 2006 American Academy of Neurology practice parameters had assigned the drug the highest level of evidence for having a significant beneficial effect, Dr. Litvan pointed out.

The FDA and the label warn that rasagiline may be associated with hypertensive crisis if patients consume tyramine-rich foods and beverages, such as aged cheese, tap beer, and red wine; dietary supplements; or amines contained in cough and cold medicines. A table of tyramine-rich food and beverages to avoid, as well as acceptable foods containing little or no tyramine, is included in the product label.

Dr. Litvan said she was surprised about the recommendation to restrict tyramine because of the selectivity of the drug. Rasagiline is more selective than selegiline (Eldepryl), which inhibits MAO-A in addition to MAO-B, she noted.

Rasagiline's label states that the drug's selectivity for inhibiting only MAO-B–not MAO-A–in humans, and a sensitivity to tyramine during treatment with rasagiline at any dose have “not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications.”

Dr. Litvan was not involved in clinical trials of the drug, and has no ties to the manufacturer, other than having received an education grant. Several of her patients who acquired the drug in Europe or Israel have done well on it, she said.

The FDA is also recommending that patients on the drug be checked regularly for signs of melanoma because people treated with rasagiline during its development were diagnosed with melanoma at a rate greater than that seen in the general population. However, the risk was comparable to that seen in some epidemiologic studies of Parkinson's patients; at this point, whether the greater melanoma rate is a result of the disease or the drug treatment is unclear. Teva will evaluate the relative risk of melanoma in a 6-month postmarketing study of rasagiline added to standard treatment in about 5,000 patients.

The recent approval of an irreversible monoamine oxidase inhibitor for treating Parkinson's disease includes an indication for patients with early disease as well as for those with more advanced disease who are already on levodopa.

Last month, the Food and Drug Administration approved rasagiline for treating the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. Rasagiline, which will be marketed under the trade name Azilect by the Israel-based company Teva Pharmaceutical Industries Ltd., will be available sometime in July, according to the company. The recommended monotherapy dose is 1 mg once daily; for adjunctive therapy, the recommended starting dose is 0.5 mg once daily, increasing to 1 mg once daily if the clinical response is not adequate.

The approval comes with a warning about the need to restrict dietary tyramine and amines contained in medications in order to avoid the risk of a hypertensive crisis, as well as a precaution about monitoring patients for melanoma.

Rasagiline–a new molecular entity that was approved in Europe and Israel last year–inhibits monoamine oxidase type B (MAO-B). Whether it is selective for and inhibits only MAO-B and not MAO-A in humans has not been adequately studied yet, according to the drug's label. The label also states that its precise mechanism of action is unknown, but is believed to be “related to inhibition of MAO-B,” which results in increased extracellular levels of dopamine in the striatum.

FDA approval was based on three 18- to 26-week, randomized, placebo-controlled studies. In the monotherapy study of 404 patients with early Parkinson's disease, those treated with rasagiline experienced significantly less worsening in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) at 6 months, when compared with those on placebo. The two other studies assessed the drug in more than 1,100 patients with more advanced disease. Study participants had had Parkinson's for an average of 9 years, were on chronic levodopa therapy, and were having motor fluctuations. Compared with those on placebo, subjects who received rasagiline had significantly less daily “off” time when their function and mobility were relatively poor.

Dr. Irene Litvan, the Raymond Lee Lebby Professor of Parkinson Disease Research at the University of Louisville (Ky.), described the approval as “great news” because the drug can be used both as monotherapy early in the course of the disease as well as an adjunct agent later in the disease's progression. In addition, the drug causes few side effects, is taken once a day, and does not need to be titrated.

Rasagiline is “an important new treatment … that can not only improve some of the symptoms of Parkinson's disease, but has the potential to slow the progression of the disease,” she said in an interview. This potential neuroprotective effect of the drug is the most exciting aspect of the approval and is what many patients have been waiting for, she added, noting that animal and in vitro data and some clinical evidence suggest rasagiline has some neuroprotective benefits.

Teva is currently recruiting patients with early idiopathic Parkinson's disease for a multinational trial to evaluate the effects of rasagiline on slowing the progression of the disease.

Even before approval, the 2006 American Academy of Neurology practice parameters had assigned the drug the highest level of evidence for having a significant beneficial effect, Dr. Litvan pointed out.

The FDA and the label warn that rasagiline may be associated with hypertensive crisis if patients consume tyramine-rich foods and beverages, such as aged cheese, tap beer, and red wine; dietary supplements; or amines contained in cough and cold medicines. A table of tyramine-rich food and beverages to avoid, as well as acceptable foods containing little or no tyramine, is included in the product label.

Dr. Litvan said she was surprised about the recommendation to restrict tyramine because of the selectivity of the drug. Rasagiline is more selective than selegiline (Eldepryl), which inhibits MAO-A in addition to MAO-B, she noted.

Rasagiline's label states that the drug's selectivity for inhibiting only MAO-B–not MAO-A–in humans, and a sensitivity to tyramine during treatment with rasagiline at any dose have “not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications.”

Dr. Litvan was not involved in clinical trials of the drug, and has no ties to the manufacturer, other than having received an education grant. Several of her patients who acquired the drug in Europe or Israel have done well on it, she said.

The FDA is also recommending that patients on the drug be checked regularly for signs of melanoma because people treated with rasagiline during its development were diagnosed with melanoma at a rate greater than that seen in the general population. However, the risk was comparable to that seen in some epidemiologic studies of Parkinson's patients; at this point, whether the greater melanoma rate is a result of the disease or the drug treatment is unclear. Teva will evaluate the relative risk of melanoma in a 6-month postmarketing study of rasagiline added to standard treatment in about 5,000 patients.

The recent approval of an irreversible monoamine oxidase inhibitor for treating Parkinson's disease includes an indication for patients with early disease as well as for those with more advanced disease who are already on levodopa.

Last month, the Food and Drug Administration approved rasagiline for treating the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. Rasagiline, which will be marketed under the trade name Azilect by the Israel-based company Teva Pharmaceutical Industries Ltd., will be available sometime in July, according to the company. The recommended monotherapy dose is 1 mg once daily; for adjunctive therapy, the recommended starting dose is 0.5 mg once daily, increasing to 1 mg once daily if the clinical response is not adequate.

The approval comes with a warning about the need to restrict dietary tyramine and amines contained in medications in order to avoid the risk of a hypertensive crisis, as well as a precaution about monitoring patients for melanoma.

Rasagiline–a new molecular entity that was approved in Europe and Israel last year–inhibits monoamine oxidase type B (MAO-B). Whether it is selective for and inhibits only MAO-B and not MAO-A in humans has not been adequately studied yet, according to the drug's label. The label also states that its precise mechanism of action is unknown, but is believed to be “related to inhibition of MAO-B,” which results in increased extracellular levels of dopamine in the striatum.

FDA approval was based on three 18- to 26-week, randomized, placebo-controlled studies. In the monotherapy study of 404 patients with early Parkinson's disease, those treated with rasagiline experienced significantly less worsening in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) at 6 months, when compared with those on placebo. The two other studies assessed the drug in more than 1,100 patients with more advanced disease. Study participants had had Parkinson's for an average of 9 years, were on chronic levodopa therapy, and were having motor fluctuations. Compared with those on placebo, subjects who received rasagiline had significantly less daily “off” time when their function and mobility were relatively poor.

Dr. Irene Litvan, the Raymond Lee Lebby Professor of Parkinson Disease Research at the University of Louisville (Ky.), described the approval as “great news” because the drug can be used both as monotherapy early in the course of the disease as well as an adjunct agent later in the disease's progression. In addition, the drug causes few side effects, is taken once a day, and does not need to be titrated.

Rasagiline is “an important new treatment … that can not only improve some of the symptoms of Parkinson's disease, but has the potential to slow the progression of the disease,” she said in an interview. This potential neuroprotective effect of the drug is the most exciting aspect of the approval and is what many patients have been waiting for, she added, noting that animal and in vitro data and some clinical evidence suggest rasagiline has some neuroprotective benefits.

Teva is currently recruiting patients with early idiopathic Parkinson's disease for a multinational trial to evaluate the effects of rasagiline on slowing the progression of the disease.

Even before approval, the 2006 American Academy of Neurology practice parameters had assigned the drug the highest level of evidence for having a significant beneficial effect, Dr. Litvan pointed out.

The FDA and the label warn that rasagiline may be associated with hypertensive crisis if patients consume tyramine-rich foods and beverages, such as aged cheese, tap beer, and red wine; dietary supplements; or amines contained in cough and cold medicines. A table of tyramine-rich food and beverages to avoid, as well as acceptable foods containing little or no tyramine, is included in the product label.

Dr. Litvan said she was surprised about the recommendation to restrict tyramine because of the selectivity of the drug. Rasagiline is more selective than selegiline (Eldepryl), which inhibits MAO-A in addition to MAO-B, she noted.

Rasagiline's label states that the drug's selectivity for inhibiting only MAO-B–not MAO-A–in humans, and a sensitivity to tyramine during treatment with rasagiline at any dose have “not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications.”

Dr. Litvan was not involved in clinical trials of the drug, and has no ties to the manufacturer, other than having received an education grant. Several of her patients who acquired the drug in Europe or Israel have done well on it, she said.

The FDA is also recommending that patients on the drug be checked regularly for signs of melanoma because people treated with rasagiline during its development were diagnosed with melanoma at a rate greater than that seen in the general population. However, the risk was comparable to that seen in some epidemiologic studies of Parkinson's patients; at this point, whether the greater melanoma rate is a result of the disease or the drug treatment is unclear. Teva will evaluate the relative risk of melanoma in a 6-month postmarketing study of rasagiline added to standard treatment in about 5,000 patients.

After several years of little indication that lamotrigine was linked to specific birth defects, a major pregnancy registry has found a significant increase in the risk of oral clefts associated with first-trimester use of lamotrigine monotherapy.

Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry detected “an elevated prevalence” of isolated, nonsyndromic oral clefts in infants exposed to lamotrigine monotherapy during the first trimester, when compared with a reference population, according to a “Dear Health Care Professional” letter issued by the drug's manufacturer, GlaxoSmithKline (GSK), last month.

The letter reports that there were five cases of oral clefts (three cleft palates and two cleft lips) among 564 pregnancies exposed to lamotrigine monotherapy in the first trimester, for a rate of 8.9/1,000. Based on these numbers, the prevalence of oral cleft is 24 times higher among lamotrigine-exposed neonates than the prevalence of 0.37/1,000 in the general population at the Brigham and Women's Hospital surveillance program, the letter says.

The letter notes that the prevalence of oral clefts in the Massachusetts General Hospital-run NAAED registry is also greater than the background prevalence of nonsyndromic oral clefts ranging from 0.50 to 2.16 per 1,000 reported in the literature, including studies from the United States, Australia, and Europe.

Lamotrigine, marketed as Lamictal by GSK, is approved as a treatment for seizures and for maintenance therapy in bipolar I disorder. It is classified as a pregnancy category C drug, and its label reads that while no evidence of teratogenicity has been found in animals, the drug has been found to reduce folate concentrations in rats, an effect “known to be associated with teratogenesis in animals and humans.”

Because there are no adequate and well-controlled studies in pregnant women, lamotrigine “should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus,” according to the label.

The five cases described in the GSK letter were reported by Dr. Lewis B. Holmes, chief of the genetics and teratology unit at Massachusetts General Hospital for Children, Boston, and director of the North American AED pregnancy registry, at the Teratology Society meeting in June.

“This was the first study big enough to be able to look at the frequency of specific major malformations,” Dr. Holmes said in an interview. He pointed out that earlier studies from the company registry and the United Kingdom registry with smaller sample sizes looked at all malformations and showed a modest increase in the rate of major malformations but did not have enough patients to pick up increases in specific malformations.

At the meeting, he reported that a greater risk of oral clefts was also detected in five other registries, suggesting the same association. In those registries, there were four oral clefts reported among 1,623 lamotrigine-exposed infants, for a frequency of 2.5/1,000 compared with 0.37/1,000 in the comparison group. “So this is something that women have to be told about,” Dr. Holmes said.

This information has to be put into a practical perspective, and physicians should discuss the absolute risk with patients, Dr. Holmes said. Based on the data he presented, the absolute risk of having an infant with an oral cleft is close to 1%—and is much less than 1% based on the other data—so “it's still a very small risk and it is a very treatable problem,” he pointed out.

Gerald G. Briggs, B.Pharm., a pharmacist clinical specialist at the Women's Pavilion, Miller Children's Hospital, Long Beach, Calif., who was at the Teratology Society meeting, said that this information “is significant because this is the first report of teratogenicity in a second-generation anticonvulsant.” All of the first-generation anticonvulsants are known to have teratogenic effects.

Furthermore, none of the women whose infants had oral clefts was a smoker, which has been associated with isolated oral clefts in some studies, and all were taking folic acid supplements at conception, so folic acid did not appear to be protective, he pointed out.

GSK's letter says the company is discussing the new data with the Food and Drug Administration and regulatory officials in other countries. GSK is encouraging physicians to register pregnant women exposed to lamotrigine before the fetal outcome is known.

GSK's Lamotrigine Pregnancy Registry can be contacted for more information at 800-336-2176. Women can enroll themselves in the NAAED registry by calling 888-233-2334.

After several years of little indication that lamotrigine was linked to specific birth defects, a major pregnancy registry has found a significant increase in the risk of oral clefts associated with first-trimester use of lamotrigine monotherapy.

Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry detected “an elevated prevalence” of isolated, nonsyndromic oral clefts in infants exposed to lamotrigine monotherapy during the first trimester, when compared with a reference population, according to a “Dear Health Care Professional” letter issued by the drug's manufacturer, GlaxoSmithKline (GSK), last month.

The letter reports that there were five cases of oral clefts (three cleft palates and two cleft lips) among 564 pregnancies exposed to lamotrigine monotherapy in the first trimester, for a rate of 8.9/1,000. Based on these numbers, the prevalence of oral cleft is 24 times higher among lamotrigine-exposed neonates than the prevalence of 0.37/1,000 in the general population at the Brigham and Women's Hospital surveillance program, the letter says.

The letter notes that the prevalence of oral clefts in the Massachusetts General Hospital-run NAAED registry is also greater than the background prevalence of nonsyndromic oral clefts ranging from 0.50 to 2.16 per 1,000 reported in the literature, including studies from the United States, Australia, and Europe.

Lamotrigine, marketed as Lamictal by GSK, is approved as a treatment for seizures and for maintenance therapy in bipolar I disorder. It is classified as a pregnancy category C drug, and its label reads that while no evidence of teratogenicity has been found in animals, the drug has been found to reduce folate concentrations in rats, an effect “known to be associated with teratogenesis in animals and humans.”

Because there are no adequate and well-controlled studies in pregnant women, lamotrigine “should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus,” according to the label.

The five cases described in the GSK letter were reported by Dr. Lewis B. Holmes, chief of the genetics and teratology unit at Massachusetts General Hospital for Children, Boston, and director of the North American AED pregnancy registry, at the Teratology Society meeting in June.

“This was the first study big enough to be able to look at the frequency of specific major malformations,” Dr. Holmes said in an interview. He pointed out that earlier studies from the company registry and the United Kingdom registry with smaller sample sizes looked at all malformations and showed a modest increase in the rate of major malformations but did not have enough patients to pick up increases in specific malformations.

At the meeting, he reported that a greater risk of oral clefts was also detected in five other registries, suggesting the same association. In those registries, there were four oral clefts reported among 1,623 lamotrigine-exposed infants, for a frequency of 2.5/1,000 compared with 0.37/1,000 in the comparison group. “So this is something that women have to be told about,” Dr. Holmes said.

This information has to be put into a practical perspective, and physicians should discuss the absolute risk with patients, Dr. Holmes said. Based on the data he presented, the absolute risk of having an infant with an oral cleft is close to 1%—and is much less than 1% based on the other data—so “it's still a very small risk and it is a very treatable problem,” he pointed out.

Gerald G. Briggs, B.Pharm., a pharmacist clinical specialist at the Women's Pavilion, Miller Children's Hospital, Long Beach, Calif., who was at the Teratology Society meeting, said that this information “is significant because this is the first report of teratogenicity in a second-generation anticonvulsant.” All of the first-generation anticonvulsants are known to have teratogenic effects.

Furthermore, none of the women whose infants had oral clefts was a smoker, which has been associated with isolated oral clefts in some studies, and all were taking folic acid supplements at conception, so folic acid did not appear to be protective, he pointed out.

GSK's letter says the company is discussing the new data with the Food and Drug Administration and regulatory officials in other countries. GSK is encouraging physicians to register pregnant women exposed to lamotrigine before the fetal outcome is known.

GSK's Lamotrigine Pregnancy Registry can be contacted for more information at 800-336-2176. Women can enroll themselves in the NAAED registry by calling 888-233-2334.

After several years of little indication that lamotrigine was linked to specific birth defects, a major pregnancy registry has found a significant increase in the risk of oral clefts associated with first-trimester use of lamotrigine monotherapy.

Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry detected “an elevated prevalence” of isolated, nonsyndromic oral clefts in infants exposed to lamotrigine monotherapy during the first trimester, when compared with a reference population, according to a “Dear Health Care Professional” letter issued by the drug's manufacturer, GlaxoSmithKline (GSK), last month.

The letter reports that there were five cases of oral clefts (three cleft palates and two cleft lips) among 564 pregnancies exposed to lamotrigine monotherapy in the first trimester, for a rate of 8.9/1,000. Based on these numbers, the prevalence of oral cleft is 24 times higher among lamotrigine-exposed neonates than the prevalence of 0.37/1,000 in the general population at the Brigham and Women's Hospital surveillance program, the letter says.

The letter notes that the prevalence of oral clefts in the Massachusetts General Hospital-run NAAED registry is also greater than the background prevalence of nonsyndromic oral clefts ranging from 0.50 to 2.16 per 1,000 reported in the literature, including studies from the United States, Australia, and Europe.

Lamotrigine, marketed as Lamictal by GSK, is approved as a treatment for seizures and for maintenance therapy in bipolar I disorder. It is classified as a pregnancy category C drug, and its label reads that while no evidence of teratogenicity has been found in animals, the drug has been found to reduce folate concentrations in rats, an effect “known to be associated with teratogenesis in animals and humans.”

Because there are no adequate and well-controlled studies in pregnant women, lamotrigine “should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus,” according to the label.

The five cases described in the GSK letter were reported by Dr. Lewis B. Holmes, chief of the genetics and teratology unit at Massachusetts General Hospital for Children, Boston, and director of the North American AED pregnancy registry, at the Teratology Society meeting in June.

“This was the first study big enough to be able to look at the frequency of specific major malformations,” Dr. Holmes said in an interview. He pointed out that earlier studies from the company registry and the United Kingdom registry with smaller sample sizes looked at all malformations and showed a modest increase in the rate of major malformations but did not have enough patients to pick up increases in specific malformations.

At the meeting, he reported that a greater risk of oral clefts was also detected in five other registries, suggesting the same association. In those registries, there were four oral clefts reported among 1,623 lamotrigine-exposed infants, for a frequency of 2.5/1,000 compared with 0.37/1,000 in the comparison group. “So this is something that women have to be told about,” Dr. Holmes said.

This information has to be put into a practical perspective, and physicians should discuss the absolute risk with patients, Dr. Holmes said. Based on the data he presented, the absolute risk of having an infant with an oral cleft is close to 1%—and is much less than 1% based on the other data—so “it's still a very small risk and it is a very treatable problem,” he pointed out.

Gerald G. Briggs, B.Pharm., a pharmacist clinical specialist at the Women's Pavilion, Miller Children's Hospital, Long Beach, Calif., who was at the Teratology Society meeting, said that this information “is significant because this is the first report of teratogenicity in a second-generation anticonvulsant.” All of the first-generation anticonvulsants are known to have teratogenic effects.

Furthermore, none of the women whose infants had oral clefts was a smoker, which has been associated with isolated oral clefts in some studies, and all were taking folic acid supplements at conception, so folic acid did not appear to be protective, he pointed out.

GSK's letter says the company is discussing the new data with the Food and Drug Administration and regulatory officials in other countries. GSK is encouraging physicians to register pregnant women exposed to lamotrigine before the fetal outcome is known.

GSK's Lamotrigine Pregnancy Registry can be contacted for more information at 800-336-2176. Women can enroll themselves in the NAAED registry by calling 888-233-2334.

Tysabri, the monoclonal antibody withdrawn from the market in February last year after progressive multifocal leukoencephalopathy was diagnosed in three patients receiving the drug in clinical trials, will be made available again for patients with relapsing forms of multiple sclerosis, under a restricted distribution program.

The Food and Drug Administration announced in June that the agency had approved Biogen Idec's application for resuming the marketing of natalizumab (Tysabri), with the risk minimization plan, a detailed multistep program called the TOUCH prescribing program by Biogen Idec, the manufacturer of Tysabri.

The FDA now requires prescribing physicians, infusion centers (or physicians' offices that provide infusions) and pharmacies that provide Tysabri to enroll in a risk-minimization program.

The purpose of the detailed, multistep program is “to ensure that physicians and patients are educated about the risks and the benefits of treatment with Tysabri and that only appropriate patients receive treatment,” Dr. Russell Katz, director of the FDA's division of neurology products, said during a teleconference held by the FDA to announce the approval to reintroduce the drug.

The program is also designed to collect information about additional cases of progressive multifocal leukoencephalopathy (PML), and other serious infections “in real time so that we can as rapidly as possible understand both what the true rate of this infection is, but also possibly whether there are any other factors” that may increase a patients risk of PML, he added.

Currently, it is not clear how to predict who will develop PML, how to prevent it, or how to treat it should it occur during treatment with Tysabri, other than to stop treatment as soon as possible, Dr. Katz said. The best estimate currently available is that the risk is about 1 per 1,000 patients treated for up to 2 years, which is based on clinical trial data on use of the drug in patients with multiple sclerosis or Crohn's disease. Little is known about the risk in a larger population or when treatment is continued for longer than 2 years, he noted.

Even with the program in place, other cases of PML are expected, including fatal cases, he said.

“This is balanced against the significant benefits that we believe the drug confers,” Dr. Katz said.

The main elements of the program are that Tysabri can be prescribed, distributed, and infused only by physicians, infusion centers, and pharmacies enrolled in the program, a process that is designed to “minimize the risk of PML, minimize death and disability due to PML, and promote informed risk-benefit decisions” regarding the use of Tysabri, according to the FDA.

A baseline MRI must be obtained in patients before treatment is started to help distinguish multiple sclerosis symptoms that may appear in the future from PML, and physicians are required to evaluate patients 3 and 6 months after the receiving the first infusion, followed by every 6 months; information from these evaluations needs to be sent to the company regularly.

Infusion centers need to inform the company each time a patient has an infusion.

Prescribing physicians are required to be able to diagnose and manage opportunistic infections and PML, or to be prepared to refer patients to an appropriate specialist.

Tysabri was approved in November 2004, and withdrawn by the manufacturer in February 2005; no new cases of PML were reported. The FDA allowed clinical trials to resume earlier this year.

More information on Tysabri, including the new label and a summary of the risk- minimization action plan, is available at www.fda.gov/cder/drug/infopage/natalizumab/default.htm

Tysabri, the monoclonal antibody withdrawn from the market in February last year after progressive multifocal leukoencephalopathy was diagnosed in three patients receiving the drug in clinical trials, will be made available again for patients with relapsing forms of multiple sclerosis, under a restricted distribution program.

The Food and Drug Administration announced in June that the agency had approved Biogen Idec's application for resuming the marketing of natalizumab (Tysabri), with the risk minimization plan, a detailed multistep program called the TOUCH prescribing program by Biogen Idec, the manufacturer of Tysabri.

The FDA now requires prescribing physicians, infusion centers (or physicians' offices that provide infusions) and pharmacies that provide Tysabri to enroll in a risk-minimization program.

The purpose of the detailed, multistep program is “to ensure that physicians and patients are educated about the risks and the benefits of treatment with Tysabri and that only appropriate patients receive treatment,” Dr. Russell Katz, director of the FDA's division of neurology products, said during a teleconference held by the FDA to announce the approval to reintroduce the drug.

The program is also designed to collect information about additional cases of progressive multifocal leukoencephalopathy (PML), and other serious infections “in real time so that we can as rapidly as possible understand both what the true rate of this infection is, but also possibly whether there are any other factors” that may increase a patients risk of PML, he added.

Currently, it is not clear how to predict who will develop PML, how to prevent it, or how to treat it should it occur during treatment with Tysabri, other than to stop treatment as soon as possible, Dr. Katz said. The best estimate currently available is that the risk is about 1 per 1,000 patients treated for up to 2 years, which is based on clinical trial data on use of the drug in patients with multiple sclerosis or Crohn's disease. Little is known about the risk in a larger population or when treatment is continued for longer than 2 years, he noted.

Even with the program in place, other cases of PML are expected, including fatal cases, he said.

“This is balanced against the significant benefits that we believe the drug confers,” Dr. Katz said.

The main elements of the program are that Tysabri can be prescribed, distributed, and infused only by physicians, infusion centers, and pharmacies enrolled in the program, a process that is designed to “minimize the risk of PML, minimize death and disability due to PML, and promote informed risk-benefit decisions” regarding the use of Tysabri, according to the FDA.

A baseline MRI must be obtained in patients before treatment is started to help distinguish multiple sclerosis symptoms that may appear in the future from PML, and physicians are required to evaluate patients 3 and 6 months after the receiving the first infusion, followed by every 6 months; information from these evaluations needs to be sent to the company regularly.

Infusion centers need to inform the company each time a patient has an infusion.

Prescribing physicians are required to be able to diagnose and manage opportunistic infections and PML, or to be prepared to refer patients to an appropriate specialist.

Tysabri was approved in November 2004, and withdrawn by the manufacturer in February 2005; no new cases of PML were reported. The FDA allowed clinical trials to resume earlier this year.

More information on Tysabri, including the new label and a summary of the risk- minimization action plan, is available at www.fda.gov/cder/drug/infopage/natalizumab/default.htm

Tysabri, the monoclonal antibody withdrawn from the market in February last year after progressive multifocal leukoencephalopathy was diagnosed in three patients receiving the drug in clinical trials, will be made available again for patients with relapsing forms of multiple sclerosis, under a restricted distribution program.

The Food and Drug Administration announced in June that the agency had approved Biogen Idec's application for resuming the marketing of natalizumab (Tysabri), with the risk minimization plan, a detailed multistep program called the TOUCH prescribing program by Biogen Idec, the manufacturer of Tysabri.

The FDA now requires prescribing physicians, infusion centers (or physicians' offices that provide infusions) and pharmacies that provide Tysabri to enroll in a risk-minimization program.

The purpose of the detailed, multistep program is “to ensure that physicians and patients are educated about the risks and the benefits of treatment with Tysabri and that only appropriate patients receive treatment,” Dr. Russell Katz, director of the FDA's division of neurology products, said during a teleconference held by the FDA to announce the approval to reintroduce the drug.

The program is also designed to collect information about additional cases of progressive multifocal leukoencephalopathy (PML), and other serious infections “in real time so that we can as rapidly as possible understand both what the true rate of this infection is, but also possibly whether there are any other factors” that may increase a patients risk of PML, he added.

Currently, it is not clear how to predict who will develop PML, how to prevent it, or how to treat it should it occur during treatment with Tysabri, other than to stop treatment as soon as possible, Dr. Katz said. The best estimate currently available is that the risk is about 1 per 1,000 patients treated for up to 2 years, which is based on clinical trial data on use of the drug in patients with multiple sclerosis or Crohn's disease. Little is known about the risk in a larger population or when treatment is continued for longer than 2 years, he noted.

Even with the program in place, other cases of PML are expected, including fatal cases, he said.

“This is balanced against the significant benefits that we believe the drug confers,” Dr. Katz said.

The main elements of the program are that Tysabri can be prescribed, distributed, and infused only by physicians, infusion centers, and pharmacies enrolled in the program, a process that is designed to “minimize the risk of PML, minimize death and disability due to PML, and promote informed risk-benefit decisions” regarding the use of Tysabri, according to the FDA.

A baseline MRI must be obtained in patients before treatment is started to help distinguish multiple sclerosis symptoms that may appear in the future from PML, and physicians are required to evaluate patients 3 and 6 months after the receiving the first infusion, followed by every 6 months; information from these evaluations needs to be sent to the company regularly.

Infusion centers need to inform the company each time a patient has an infusion.

Prescribing physicians are required to be able to diagnose and manage opportunistic infections and PML, or to be prepared to refer patients to an appropriate specialist.

Tysabri was approved in November 2004, and withdrawn by the manufacturer in February 2005; no new cases of PML were reported. The FDA allowed clinical trials to resume earlier this year.

More information on Tysabri, including the new label and a summary of the risk- minimization action plan, is available at www.fda.gov/cder/drug/infopage/natalizumab/default.htm

GAITHERSBURG, MD. – The cholinesterase inhibitor rivastigmine is likely to be approved for a second indication: the treatment of mild to moderate dementia associated with Parkinson's disease, based on a study that found treatment was associated with significant benefits in cognition, behavior, and activities of daily living in such patients.

Only one study of rivastigmine–the EXPRESS trial–has been submitted to the Food and Drug Administration for approval of the new indication. However, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee unanimously agreed that the study was well designed for evaluating the efficacy and safety of the drug in treating mild to moderate dementia associated with Parkinson's, the indication proposed for approval by the manufacturer, Novartis Pharmaceuticals. Usually two studies are submitted to the FDA for consideration for approving a drug.

The panel was not asked to specifically vote on whether to recommend approval, but all eight panelists at the meeting agreed that the overall data indicated that rivastigmine, at a dose of 3–12 mg per day, was safe in this population. The panel voted 7 to 0 with one abstention that, based on its results, the study did not need to be replicated for the FDA to approve the new indication.

“What convinces me that one study is enough” is the amount of safety data available for its use in Alzheimer's disease and “robust finding[s] on all secondary end points” for Parkinson's dementia, which were congruous with findings on the primary end points, said panel member Dr. Ralph L. Sacco, professor of neurology and epidemiology at the Neurological Institute of New York at Columbia University.

Novartis markets rivastigmine as Exelon, which was approved in the United States in 2000 for mild to moderate dementia of the Alzheimer's type. It was approved for the Parkinson's indication in the European Union earlier this year, but there are no treatments currently approved for this indication in the United States. The FDA usually follows the recommendations of its advisory panels.

The EXPRESS study compared the impact of rivastigmine with that of placebo over 24 weeks in 541 patients with mild to moderate dementia (362 on treatment, 179 on placebo) with a mean age of 72 years. They had been diagnosed with Parkinson's a mean of about 9 years earlier, and a mean of about 7 years had elapsed between their diagnosis and the appearance of the first dementia symptoms.

At 24 weeks, changes from baseline in the primary efficacy outcome end points, two subscales of the Alzheimer Disease Assessment Scale (ADAS) that assessed cognition and overall dementia, significantly favored those treated with rivastigmine. The secondary outcome measures of activities of daily living, executive function, attention, and behavior at 24 weeks were also significantly improved among the treated patients.

Among those on rivastigmine, 27% discontinued treatment, compared with 18% of those in the placebo group; in both groups, most discontinued because of an adverse event. During the study and an extension study that followed patients for another 48 weeks, the most frequent side effects among treated patients were cholinergic, including nausea (29%), vomiting (17%), and worsening tremor (10%), which in most cases were mild to moderate and infrequently resulted in discontinuing treatment, according to Novartis.

Speaking on behalf of Novartis at the meeting, Dr. Clive Ballard, professor of age-related diseases at the Institute of Psychiatry, King's College, London, described Parkinson's dementia as a distinct dementia syndrome that can be “unambiguously diagnosed in routine clinical practice” by using three principles: The patient has an established diagnosis of idiopathic Parkinson's disease, develops dementia at least 1–2 years after the onset of PD, and has had other causes of dementia excluded.

Autopsy studies indicate that these criteria accurately diagnose 90% of cases, he said, adding that there is emerging evidence that a cholinergic deficit, shared by PD and Alzheimer's, is associated with many of the key cognitive deficits and neuropsychiatric symptoms.

In a unanimous vote, the panel agreed that there was a separate form of dementia associated with Parkinson's that is distinct from Alzheimer's disease, and that there are operational criteria that could be used for making the diagnosis clinically.

Dr. Russell Katz, director of the FDA's division of neurology products, explained that FDA reviewers had wanted to know whether the panel believed that the average practicing neurologist could reliably diagnose dementia in these patients and distinguish it from Alzheimer's dementia using the algorithm described by the company.

Panel member Dr. J. Eric Ahlskog, professor of neurology at the Mayo Clinic, Rochester, Minn., said that although clinicians in a busy clinic may not be good at sorting out specific changes such as changes in executive function, “we are pretty good as neurologists in saying yes, this person is demented.” He agreed that the type of dementia could be ascertained by the two-step process of determining whether a patient has Parkinson's and whether he or she has developed dementia after an interval of time.

Panel member Dr. Irene Litvan, director of the movement disorders program at the University of Louisville (Kentucky), said she agreed that Parkinson's disease dementia is “a clear neurological entity.”

While criteria for making the clinical diagnosis of dementia associated with Parkinson's are needed, Dr. Litvan, who is Raymond Lee Lebby professor of Parkinson's disease research at the university, said that for now, she “believe[s] that a neurologist will be able to apply the simple criteria and make a diagnosis of Parkinson's disease dementia and be able to treat it.”

GAITHERSBURG, MD. – The cholinesterase inhibitor rivastigmine is likely to be approved for a second indication: the treatment of mild to moderate dementia associated with Parkinson's disease, based on a study that found treatment was associated with significant benefits in cognition, behavior, and activities of daily living in such patients.

Only one study of rivastigmine–the EXPRESS trial–has been submitted to the Food and Drug Administration for approval of the new indication. However, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee unanimously agreed that the study was well designed for evaluating the efficacy and safety of the drug in treating mild to moderate dementia associated with Parkinson's, the indication proposed for approval by the manufacturer, Novartis Pharmaceuticals. Usually two studies are submitted to the FDA for consideration for approving a drug.

The panel was not asked to specifically vote on whether to recommend approval, but all eight panelists at the meeting agreed that the overall data indicated that rivastigmine, at a dose of 3–12 mg per day, was safe in this population. The panel voted 7 to 0 with one abstention that, based on its results, the study did not need to be replicated for the FDA to approve the new indication.

“What convinces me that one study is enough” is the amount of safety data available for its use in Alzheimer's disease and “robust finding[s] on all secondary end points” for Parkinson's dementia, which were congruous with findings on the primary end points, said panel member Dr. Ralph L. Sacco, professor of neurology and epidemiology at the Neurological Institute of New York at Columbia University.

Novartis markets rivastigmine as Exelon, which was approved in the United States in 2000 for mild to moderate dementia of the Alzheimer's type. It was approved for the Parkinson's indication in the European Union earlier this year, but there are no treatments currently approved for this indication in the United States. The FDA usually follows the recommendations of its advisory panels.

The EXPRESS study compared the impact of rivastigmine with that of placebo over 24 weeks in 541 patients with mild to moderate dementia (362 on treatment, 179 on placebo) with a mean age of 72 years. They had been diagnosed with Parkinson's a mean of about 9 years earlier, and a mean of about 7 years had elapsed between their diagnosis and the appearance of the first dementia symptoms.

At 24 weeks, changes from baseline in the primary efficacy outcome end points, two subscales of the Alzheimer Disease Assessment Scale (ADAS) that assessed cognition and overall dementia, significantly favored those treated with rivastigmine. The secondary outcome measures of activities of daily living, executive function, attention, and behavior at 24 weeks were also significantly improved among the treated patients.

Among those on rivastigmine, 27% discontinued treatment, compared with 18% of those in the placebo group; in both groups, most discontinued because of an adverse event. During the study and an extension study that followed patients for another 48 weeks, the most frequent side effects among treated patients were cholinergic, including nausea (29%), vomiting (17%), and worsening tremor (10%), which in most cases were mild to moderate and infrequently resulted in discontinuing treatment, according to Novartis.

Speaking on behalf of Novartis at the meeting, Dr. Clive Ballard, professor of age-related diseases at the Institute of Psychiatry, King's College, London, described Parkinson's dementia as a distinct dementia syndrome that can be “unambiguously diagnosed in routine clinical practice” by using three principles: The patient has an established diagnosis of idiopathic Parkinson's disease, develops dementia at least 1–2 years after the onset of PD, and has had other causes of dementia excluded.

Autopsy studies indicate that these criteria accurately diagnose 90% of cases, he said, adding that there is emerging evidence that a cholinergic deficit, shared by PD and Alzheimer's, is associated with many of the key cognitive deficits and neuropsychiatric symptoms.

In a unanimous vote, the panel agreed that there was a separate form of dementia associated with Parkinson's that is distinct from Alzheimer's disease, and that there are operational criteria that could be used for making the diagnosis clinically.

Dr. Russell Katz, director of the FDA's division of neurology products, explained that FDA reviewers had wanted to know whether the panel believed that the average practicing neurologist could reliably diagnose dementia in these patients and distinguish it from Alzheimer's dementia using the algorithm described by the company.

Panel member Dr. J. Eric Ahlskog, professor of neurology at the Mayo Clinic, Rochester, Minn., said that although clinicians in a busy clinic may not be good at sorting out specific changes such as changes in executive function, “we are pretty good as neurologists in saying yes, this person is demented.” He agreed that the type of dementia could be ascertained by the two-step process of determining whether a patient has Parkinson's and whether he or she has developed dementia after an interval of time.

Panel member Dr. Irene Litvan, director of the movement disorders program at the University of Louisville (Kentucky), said she agreed that Parkinson's disease dementia is “a clear neurological entity.”

While criteria for making the clinical diagnosis of dementia associated with Parkinson's are needed, Dr. Litvan, who is Raymond Lee Lebby professor of Parkinson's disease research at the university, said that for now, she “believe[s] that a neurologist will be able to apply the simple criteria and make a diagnosis of Parkinson's disease dementia and be able to treat it.”

GAITHERSBURG, MD. – The cholinesterase inhibitor rivastigmine is likely to be approved for a second indication: the treatment of mild to moderate dementia associated with Parkinson's disease, based on a study that found treatment was associated with significant benefits in cognition, behavior, and activities of daily living in such patients.

Only one study of rivastigmine–the EXPRESS trial–has been submitted to the Food and Drug Administration for approval of the new indication. However, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee unanimously agreed that the study was well designed for evaluating the efficacy and safety of the drug in treating mild to moderate dementia associated with Parkinson's, the indication proposed for approval by the manufacturer, Novartis Pharmaceuticals. Usually two studies are submitted to the FDA for consideration for approving a drug.

The panel was not asked to specifically vote on whether to recommend approval, but all eight panelists at the meeting agreed that the overall data indicated that rivastigmine, at a dose of 3–12 mg per day, was safe in this population. The panel voted 7 to 0 with one abstention that, based on its results, the study did not need to be replicated for the FDA to approve the new indication.

“What convinces me that one study is enough” is the amount of safety data available for its use in Alzheimer's disease and “robust finding[s] on all secondary end points” for Parkinson's dementia, which were congruous with findings on the primary end points, said panel member Dr. Ralph L. Sacco, professor of neurology and epidemiology at the Neurological Institute of New York at Columbia University.

Novartis markets rivastigmine as Exelon, which was approved in the United States in 2000 for mild to moderate dementia of the Alzheimer's type. It was approved for the Parkinson's indication in the European Union earlier this year, but there are no treatments currently approved for this indication in the United States. The FDA usually follows the recommendations of its advisory panels.

The EXPRESS study compared the impact of rivastigmine with that of placebo over 24 weeks in 541 patients with mild to moderate dementia (362 on treatment, 179 on placebo) with a mean age of 72 years. They had been diagnosed with Parkinson's a mean of about 9 years earlier, and a mean of about 7 years had elapsed between their diagnosis and the appearance of the first dementia symptoms.

At 24 weeks, changes from baseline in the primary efficacy outcome end points, two subscales of the Alzheimer Disease Assessment Scale (ADAS) that assessed cognition and overall dementia, significantly favored those treated with rivastigmine. The secondary outcome measures of activities of daily living, executive function, attention, and behavior at 24 weeks were also significantly improved among the treated patients.

Among those on rivastigmine, 27% discontinued treatment, compared with 18% of those in the placebo group; in both groups, most discontinued because of an adverse event. During the study and an extension study that followed patients for another 48 weeks, the most frequent side effects among treated patients were cholinergic, including nausea (29%), vomiting (17%), and worsening tremor (10%), which in most cases were mild to moderate and infrequently resulted in discontinuing treatment, according to Novartis.

Speaking on behalf of Novartis at the meeting, Dr. Clive Ballard, professor of age-related diseases at the Institute of Psychiatry, King's College, London, described Parkinson's dementia as a distinct dementia syndrome that can be “unambiguously diagnosed in routine clinical practice” by using three principles: The patient has an established diagnosis of idiopathic Parkinson's disease, develops dementia at least 1–2 years after the onset of PD, and has had other causes of dementia excluded.

Autopsy studies indicate that these criteria accurately diagnose 90% of cases, he said, adding that there is emerging evidence that a cholinergic deficit, shared by PD and Alzheimer's, is associated with many of the key cognitive deficits and neuropsychiatric symptoms.

In a unanimous vote, the panel agreed that there was a separate form of dementia associated with Parkinson's that is distinct from Alzheimer's disease, and that there are operational criteria that could be used for making the diagnosis clinically.

Dr. Russell Katz, director of the FDA's division of neurology products, explained that FDA reviewers had wanted to know whether the panel believed that the average practicing neurologist could reliably diagnose dementia in these patients and distinguish it from Alzheimer's dementia using the algorithm described by the company.

Panel member Dr. J. Eric Ahlskog, professor of neurology at the Mayo Clinic, Rochester, Minn., said that although clinicians in a busy clinic may not be good at sorting out specific changes such as changes in executive function, “we are pretty good as neurologists in saying yes, this person is demented.” He agreed that the type of dementia could be ascertained by the two-step process of determining whether a patient has Parkinson's and whether he or she has developed dementia after an interval of time.

Panel member Dr. Irene Litvan, director of the movement disorders program at the University of Louisville (Kentucky), said she agreed that Parkinson's disease dementia is “a clear neurological entity.”

While criteria for making the clinical diagnosis of dementia associated with Parkinson's are needed, Dr. Litvan, who is Raymond Lee Lebby professor of Parkinson's disease research at the university, said that for now, she “believe[s] that a neurologist will be able to apply the simple criteria and make a diagnosis of Parkinson's disease dementia and be able to treat it.”

The recent approval of an irreversible monoamine oxidase inhibitor for treating Parkinson's disease includes an indication for patients with early disease as well as for those with more advanced disease who are already on levodopa.

The Food and Drug Administration approved rasagiline for treating the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. Rasagiline, which will be marketed under the trade name Azilect by the Israel-based company Teva Pharmaceutical Industries Ltd., will be available sometime in July, according to the company. The recommended monotherapy dose is 1 mg once daily; for adjunctive therapy, the recommended starting dose is 0.5 mg once daily, increasing to 1 mg once daily if the clinical response is not adequate.

The approval comes with a warning about the need to restrict dietary tyramine and amines contained in medications in order to avoid the risk of a hypertensive crisis, as well as a precaution about monitoring patients for melanoma.

Rasagiline—a new molecular entity that was approved in Europe and Israel last year—inhibits monoamine oxidase type B (MAO-B). Whether it is selective for and inhibits only MAO-B and not MAO-A in humans has not been adequately studied yet, according to the drug's label. The label also states that its precise mechanism of action is unknown, but is believed to be “related to inhibition of MAO-B,” which results in increased extracellular levels of dopamine in the striatum.

FDA approval was based on three 18- to 26-week, randomized, placebo-controlled studies. In the monotherapy study of 404 patients with early Parkinson's disease, those treated with rasagiline experienced significantly less worsening in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) at 6 months, when compared with those on placebo. The two other studies assessed the drug in more than 1,100 patients with more advanced disease. Study participants had had Parkinson's for an average of 9 years, were on chronic levodopa therapy, and were having motor fluctuations. Compared with those on placebo, subjects who received rasagiline had significantly less daily “off” time when their function and mobility were relatively poor.

Dr. Irene Litvan, the Raymond Lee Lebby Professor of Parkinson Disease Research at the University of Louisville (Ky.), described the approval as “great news” because the drug can be used both as monotherapy early in the course of the disease as well as an adjunct agent later in the disease's progression. In addition, the drug causes few side effects, is taken once a day, and does not need to be titrated.

Rasagiline is “an important new treatment … that can not only improve some of the symptoms of Parkinson's disease, but has the potential to slow the progression of the disease,” she said in an interview. This potential neuroprotective effect of the drug is the most exciting aspect of the approval and is what many patients have been waiting for, she added, noting that animal and in vitro data and some clinical evidence suggest rasagiline has some neuroprotective benefits.

Teva is currently recruiting patients with early idiopathic Parkinson's disease for a multinational trial to evaluate the effects of rasagiline on slowing the progression of the disease.

Even before approval, the 2006 American Academy of Neurology practice parameters had assigned the drug the highest level of evidence for having a significant beneficial effect, Dr. Litvan pointed out.

The FDA and the label warn that rasagiline may be associated with hypertensive crisis if patients consume tyramine-rich foods and beverages, such as aged cheese, tap beer, and red wine; dietary supplements; or amines contained in cough and cold medicines. A table of tyramine-rich food and beverages to avoid, as well as acceptable foods containing little or no tyramine, is included in the product label.

Dr. Litvan said she was surprised about the recommendation to restrict tyramine because of the selectivity of the drug. Rasagiline is more selective than selegiline (Eldepryl), which inhibits MAO-A in addition to MAO-B, she noted.

Rasagiline's label states that the drug's selectivity for inhibiting only MAO-B—not MAO-A—in humans, and a sensitivity to tyramine during treatment with rasagiline at any dose have “not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications.”

Dr. Litvan was not involved in clinical trials of the drug, and has no ties to the manufacturer, other than having received an education grant. Several of her patients who acquired the drug in Europe or Israel have done well on it, she said.

The FDA is also recommending that patients on the drug be checked regularly for signs of melanoma because people treated with rasagiline during its development were diagnosed with melanoma at a rate greater than that seen in the general population. However, the risk was comparable to that seen in some epidemiologic studies of Parkinson's disease patients; at this point, whether the greater melanoma rate is a result of the disease or the drug treatment is unclear. Teva will evaluate the relative risk of melanoma in a 6-month postmarketing study of rasagiline added to standard treatment, in about 5,000 patients.

The recent approval of an irreversible monoamine oxidase inhibitor for treating Parkinson's disease includes an indication for patients with early disease as well as for those with more advanced disease who are already on levodopa.

The Food and Drug Administration approved rasagiline for treating the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. Rasagiline, which will be marketed under the trade name Azilect by the Israel-based company Teva Pharmaceutical Industries Ltd., will be available sometime in July, according to the company. The recommended monotherapy dose is 1 mg once daily; for adjunctive therapy, the recommended starting dose is 0.5 mg once daily, increasing to 1 mg once daily if the clinical response is not adequate.

The approval comes with a warning about the need to restrict dietary tyramine and amines contained in medications in order to avoid the risk of a hypertensive crisis, as well as a precaution about monitoring patients for melanoma.

Rasagiline—a new molecular entity that was approved in Europe and Israel last year—inhibits monoamine oxidase type B (MAO-B). Whether it is selective for and inhibits only MAO-B and not MAO-A in humans has not been adequately studied yet, according to the drug's label. The label also states that its precise mechanism of action is unknown, but is believed to be “related to inhibition of MAO-B,” which results in increased extracellular levels of dopamine in the striatum.

FDA approval was based on three 18- to 26-week, randomized, placebo-controlled studies. In the monotherapy study of 404 patients with early Parkinson's disease, those treated with rasagiline experienced significantly less worsening in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) at 6 months, when compared with those on placebo. The two other studies assessed the drug in more than 1,100 patients with more advanced disease. Study participants had had Parkinson's for an average of 9 years, were on chronic levodopa therapy, and were having motor fluctuations. Compared with those on placebo, subjects who received rasagiline had significantly less daily “off” time when their function and mobility were relatively poor.

Dr. Irene Litvan, the Raymond Lee Lebby Professor of Parkinson Disease Research at the University of Louisville (Ky.), described the approval as “great news” because the drug can be used both as monotherapy early in the course of the disease as well as an adjunct agent later in the disease's progression. In addition, the drug causes few side effects, is taken once a day, and does not need to be titrated.

Rasagiline is “an important new treatment … that can not only improve some of the symptoms of Parkinson's disease, but has the potential to slow the progression of the disease,” she said in an interview. This potential neuroprotective effect of the drug is the most exciting aspect of the approval and is what many patients have been waiting for, she added, noting that animal and in vitro data and some clinical evidence suggest rasagiline has some neuroprotective benefits.

Teva is currently recruiting patients with early idiopathic Parkinson's disease for a multinational trial to evaluate the effects of rasagiline on slowing the progression of the disease.

Even before approval, the 2006 American Academy of Neurology practice parameters had assigned the drug the highest level of evidence for having a significant beneficial effect, Dr. Litvan pointed out.

The FDA and the label warn that rasagiline may be associated with hypertensive crisis if patients consume tyramine-rich foods and beverages, such as aged cheese, tap beer, and red wine; dietary supplements; or amines contained in cough and cold medicines. A table of tyramine-rich food and beverages to avoid, as well as acceptable foods containing little or no tyramine, is included in the product label.

Dr. Litvan said she was surprised about the recommendation to restrict tyramine because of the selectivity of the drug. Rasagiline is more selective than selegiline (Eldepryl), which inhibits MAO-A in addition to MAO-B, she noted.

Rasagiline's label states that the drug's selectivity for inhibiting only MAO-B—not MAO-A—in humans, and a sensitivity to tyramine during treatment with rasagiline at any dose have “not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications.”

Dr. Litvan was not involved in clinical trials of the drug, and has no ties to the manufacturer, other than having received an education grant. Several of her patients who acquired the drug in Europe or Israel have done well on it, she said.

The FDA is also recommending that patients on the drug be checked regularly for signs of melanoma because people treated with rasagiline during its development were diagnosed with melanoma at a rate greater than that seen in the general population. However, the risk was comparable to that seen in some epidemiologic studies of Parkinson's disease patients; at this point, whether the greater melanoma rate is a result of the disease or the drug treatment is unclear. Teva will evaluate the relative risk of melanoma in a 6-month postmarketing study of rasagiline added to standard treatment, in about 5,000 patients.

The recent approval of an irreversible monoamine oxidase inhibitor for treating Parkinson's disease includes an indication for patients with early disease as well as for those with more advanced disease who are already on levodopa.

The Food and Drug Administration approved rasagiline for treating the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. Rasagiline, which will be marketed under the trade name Azilect by the Israel-based company Teva Pharmaceutical Industries Ltd., will be available sometime in July, according to the company. The recommended monotherapy dose is 1 mg once daily; for adjunctive therapy, the recommended starting dose is 0.5 mg once daily, increasing to 1 mg once daily if the clinical response is not adequate.

The approval comes with a warning about the need to restrict dietary tyramine and amines contained in medications in order to avoid the risk of a hypertensive crisis, as well as a precaution about monitoring patients for melanoma.

Rasagiline—a new molecular entity that was approved in Europe and Israel last year—inhibits monoamine oxidase type B (MAO-B). Whether it is selective for and inhibits only MAO-B and not MAO-A in humans has not been adequately studied yet, according to the drug's label. The label also states that its precise mechanism of action is unknown, but is believed to be “related to inhibition of MAO-B,” which results in increased extracellular levels of dopamine in the striatum.

FDA approval was based on three 18- to 26-week, randomized, placebo-controlled studies. In the monotherapy study of 404 patients with early Parkinson's disease, those treated with rasagiline experienced significantly less worsening in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) at 6 months, when compared with those on placebo. The two other studies assessed the drug in more than 1,100 patients with more advanced disease. Study participants had had Parkinson's for an average of 9 years, were on chronic levodopa therapy, and were having motor fluctuations. Compared with those on placebo, subjects who received rasagiline had significantly less daily “off” time when their function and mobility were relatively poor.

Dr. Irene Litvan, the Raymond Lee Lebby Professor of Parkinson Disease Research at the University of Louisville (Ky.), described the approval as “great news” because the drug can be used both as monotherapy early in the course of the disease as well as an adjunct agent later in the disease's progression. In addition, the drug causes few side effects, is taken once a day, and does not need to be titrated.

Rasagiline is “an important new treatment … that can not only improve some of the symptoms of Parkinson's disease, but has the potential to slow the progression of the disease,” she said in an interview. This potential neuroprotective effect of the drug is the most exciting aspect of the approval and is what many patients have been waiting for, she added, noting that animal and in vitro data and some clinical evidence suggest rasagiline has some neuroprotective benefits.

Teva is currently recruiting patients with early idiopathic Parkinson's disease for a multinational trial to evaluate the effects of rasagiline on slowing the progression of the disease.

Even before approval, the 2006 American Academy of Neurology practice parameters had assigned the drug the highest level of evidence for having a significant beneficial effect, Dr. Litvan pointed out.

The FDA and the label warn that rasagiline may be associated with hypertensive crisis if patients consume tyramine-rich foods and beverages, such as aged cheese, tap beer, and red wine; dietary supplements; or amines contained in cough and cold medicines. A table of tyramine-rich food and beverages to avoid, as well as acceptable foods containing little or no tyramine, is included in the product label.

Dr. Litvan said she was surprised about the recommendation to restrict tyramine because of the selectivity of the drug. Rasagiline is more selective than selegiline (Eldepryl), which inhibits MAO-A in addition to MAO-B, she noted.

Rasagiline's label states that the drug's selectivity for inhibiting only MAO-B—not MAO-A—in humans, and a sensitivity to tyramine during treatment with rasagiline at any dose have “not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications.”

Dr. Litvan was not involved in clinical trials of the drug, and has no ties to the manufacturer, other than having received an education grant. Several of her patients who acquired the drug in Europe or Israel have done well on it, she said.

The FDA is also recommending that patients on the drug be checked regularly for signs of melanoma because people treated with rasagiline during its development were diagnosed with melanoma at a rate greater than that seen in the general population. However, the risk was comparable to that seen in some epidemiologic studies of Parkinson's disease patients; at this point, whether the greater melanoma rate is a result of the disease or the drug treatment is unclear. Teva will evaluate the relative risk of melanoma in a 6-month postmarketing study of rasagiline added to standard treatment, in about 5,000 patients.

GAITHERSBURG, MD.—The Food and Drug Administration is paving the way for information on the clinical benefits of antihypertensive drugs to be included in their labels because it is concerned that hypertension is seriously undertreated.

The FDA's division of Cardiovascular and Renal Drug Products has prepared a draft guidance document for industry, which is intended as a guide for adding outcome claims to the labels of antihypertensive drugs. The draft was set to be published in the Federal Register by the end of May. Such guidance documents are considered recommendations and are not required.

Most labels of antihypertensive drugs, aimed at physicians, do not elaborate on the well-established clinical benefits that result from reducing blood pressure. But the agency “believes that, by making the connection between lower blood pressure and improved outcomes more explicit in labeling, it can encourage appropriate use of these drugs,” according to a statement in the guidance document. This statement and the other elements of the draft guidance were reviewed by the FDA's Cardiovascular and Renal Drugs Advisory Committee, at a meeting of the panel in April.

The proposed indications section includes such statements as: “drug name” is indicated for treating hypertension, “to reduce the risk of cardiovascular events, primarily fatal and nonfatal strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacological classes (including this drug) including the class to which this drug principally belongs.”

The panel reviewed specific sections of the proposed clinical trials section of the label, which includes the statement that high systolic or diastolic blood pressure increases cardiovascular risk, and the “risk increase per mm Hg is greater at higher blood pressures.” The section also says many drugs in various pharmacologic classes, “whose only common property is to lower blood pressure, have been shown to reduce cardiovascular morbidity and mortality, and it can be concluded that the blood pressure reduction is responsible for those benefits.” The reduced risk of stroke is “the largest and most consistent outcome benefit … but reductions in myocardial infarction and cardiovascular mortality have also often been seen.”

The proposed label would also include a statement if there were no outcome trials that had been conducted for the particular drug or drug class, which had shown reductions in cardiovascular risk in hypertensive patients.

Other elements of the clinical trial section include references to the need for combination therapy in many patients, the smaller effects of some agents in black patients, and the additional effects of many antihypertensive drugs on outcomes such as angina, heart failure, or diabetic kidney disease. Among panelists' concerns were that there should be a qualifier for new drugs and an adequate amount of safety data on new drugs.

In an interview, Dr. John M. Flack, professor of medicine and physiology and interim chair and chief of translational research and clinical epidemiology at Wayne State University, Detroit, said more explicit labeling of the cardiovascular risk reduction expected from lowering blood pressure will have a positive impact on physician prescribing patterns, and “enhance the likelihood of doctors taking these drugs more seriously.” Dr. Flack, a member of the FDA panel, was recused for this session, but was at the meeting.

The data strongly suggests that for a host of drugs across different classes that are mechanistically dissimilar, when they lower blood pressure, they lower cardiovascular risk as well, he said. At the very least, the enhanced label would have a neutral effect, and won't cause any harm, but adding the information on outcome claims “has the potential to improve the use of these drugs in a very treatable but undertreated condition,” Dr. Flack noted.

GAITHERSBURG, MD.—The Food and Drug Administration is paving the way for information on the clinical benefits of antihypertensive drugs to be included in their labels because it is concerned that hypertension is seriously undertreated.

The FDA's division of Cardiovascular and Renal Drug Products has prepared a draft guidance document for industry, which is intended as a guide for adding outcome claims to the labels of antihypertensive drugs. The draft was set to be published in the Federal Register by the end of May. Such guidance documents are considered recommendations and are not required.

Most labels of antihypertensive drugs, aimed at physicians, do not elaborate on the well-established clinical benefits that result from reducing blood pressure. But the agency “believes that, by making the connection between lower blood pressure and improved outcomes more explicit in labeling, it can encourage appropriate use of these drugs,” according to a statement in the guidance document. This statement and the other elements of the draft guidance were reviewed by the FDA's Cardiovascular and Renal Drugs Advisory Committee, at a meeting of the panel in April.

The proposed indications section includes such statements as: “drug name” is indicated for treating hypertension, “to reduce the risk of cardiovascular events, primarily fatal and nonfatal strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacological classes (including this drug) including the class to which this drug principally belongs.”

The panel reviewed specific sections of the proposed clinical trials section of the label, which includes the statement that high systolic or diastolic blood pressure increases cardiovascular risk, and the “risk increase per mm Hg is greater at higher blood pressures.” The section also says many drugs in various pharmacologic classes, “whose only common property is to lower blood pressure, have been shown to reduce cardiovascular morbidity and mortality, and it can be concluded that the blood pressure reduction is responsible for those benefits.” The reduced risk of stroke is “the largest and most consistent outcome benefit … but reductions in myocardial infarction and cardiovascular mortality have also often been seen.”

The proposed label would also include a statement if there were no outcome trials that had been conducted for the particular drug or drug class, which had shown reductions in cardiovascular risk in hypertensive patients.

Other elements of the clinical trial section include references to the need for combination therapy in many patients, the smaller effects of some agents in black patients, and the additional effects of many antihypertensive drugs on outcomes such as angina, heart failure, or diabetic kidney disease. Among panelists' concerns were that there should be a qualifier for new drugs and an adequate amount of safety data on new drugs.

In an interview, Dr. John M. Flack, professor of medicine and physiology and interim chair and chief of translational research and clinical epidemiology at Wayne State University, Detroit, said more explicit labeling of the cardiovascular risk reduction expected from lowering blood pressure will have a positive impact on physician prescribing patterns, and “enhance the likelihood of doctors taking these drugs more seriously.” Dr. Flack, a member of the FDA panel, was recused for this session, but was at the meeting.

The data strongly suggests that for a host of drugs across different classes that are mechanistically dissimilar, when they lower blood pressure, they lower cardiovascular risk as well, he said. At the very least, the enhanced label would have a neutral effect, and won't cause any harm, but adding the information on outcome claims “has the potential to improve the use of these drugs in a very treatable but undertreated condition,” Dr. Flack noted.

GAITHERSBURG, MD.—The Food and Drug Administration is paving the way for information on the clinical benefits of antihypertensive drugs to be included in their labels because it is concerned that hypertension is seriously undertreated.

The FDA's division of Cardiovascular and Renal Drug Products has prepared a draft guidance document for industry, which is intended as a guide for adding outcome claims to the labels of antihypertensive drugs. The draft was set to be published in the Federal Register by the end of May. Such guidance documents are considered recommendations and are not required.

Most labels of antihypertensive drugs, aimed at physicians, do not elaborate on the well-established clinical benefits that result from reducing blood pressure. But the agency “believes that, by making the connection between lower blood pressure and improved outcomes more explicit in labeling, it can encourage appropriate use of these drugs,” according to a statement in the guidance document. This statement and the other elements of the draft guidance were reviewed by the FDA's Cardiovascular and Renal Drugs Advisory Committee, at a meeting of the panel in April.

The proposed indications section includes such statements as: “drug name” is indicated for treating hypertension, “to reduce the risk of cardiovascular events, primarily fatal and nonfatal strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacological classes (including this drug) including the class to which this drug principally belongs.”

The panel reviewed specific sections of the proposed clinical trials section of the label, which includes the statement that high systolic or diastolic blood pressure increases cardiovascular risk, and the “risk increase per mm Hg is greater at higher blood pressures.” The section also says many drugs in various pharmacologic classes, “whose only common property is to lower blood pressure, have been shown to reduce cardiovascular morbidity and mortality, and it can be concluded that the blood pressure reduction is responsible for those benefits.” The reduced risk of stroke is “the largest and most consistent outcome benefit … but reductions in myocardial infarction and cardiovascular mortality have also often been seen.”

The proposed label would also include a statement if there were no outcome trials that had been conducted for the particular drug or drug class, which had shown reductions in cardiovascular risk in hypertensive patients.

Other elements of the clinical trial section include references to the need for combination therapy in many patients, the smaller effects of some agents in black patients, and the additional effects of many antihypertensive drugs on outcomes such as angina, heart failure, or diabetic kidney disease. Among panelists' concerns were that there should be a qualifier for new drugs and an adequate amount of safety data on new drugs.

In an interview, Dr. John M. Flack, professor of medicine and physiology and interim chair and chief of translational research and clinical epidemiology at Wayne State University, Detroit, said more explicit labeling of the cardiovascular risk reduction expected from lowering blood pressure will have a positive impact on physician prescribing patterns, and “enhance the likelihood of doctors taking these drugs more seriously.” Dr. Flack, a member of the FDA panel, was recused for this session, but was at the meeting.

The data strongly suggests that for a host of drugs across different classes that are mechanistically dissimilar, when they lower blood pressure, they lower cardiovascular risk as well, he said. At the very least, the enhanced label would have a neutral effect, and won't cause any harm, but adding the information on outcome claims “has the potential to improve the use of these drugs in a very treatable but undertreated condition,” Dr. Flack noted.

The Food and Drug Administration has approved the immunosuppressant tacrolimus for preventing rejection in heart transplant recipients, on the basis of studies that found similar rates of patient and graft survival in patients on tacrolimus-based regimens and cyclosporine-based regimens.

Tacrolimus, marketed as Prograf by Astellas Pharma US, was previously approved for preventing rejection in kidney and liver transplant recipients and has been increasingly used off label for heart transplant recipients over the past several years.

During this time, “tacrolimus has been gaining favor as the first-line drug of choice,” said Dr. Jon Kobashigawa, medical director of the University of California, Los Angeles, heart transplant program, where a switch from a cyclosporine-based regimen to a tacrolimus-based regimen, usually with mycophenolate mofetil (MMF), was made about 5 years ago. After reports found it effective in reversing recurrent or refractory rejection, its use for primary prevention was studied in several trials, which demonstrated that a tacrolimus-based regimen was at least as effective as cyclosporine-based regimens, he said in an interview.

Two studies published in April in the American Journal of Transplantation demonstrated that the tacrolimus-based regimen was more effective in reducing rejection and had fewer side effects than did the cyclosporine-based regimen, said Dr. Kobashigawa, a principal investigator of one of these studies. He has received research grants and speaker honoraria from Astellas, and is on the company's scientific advisory board.

The incidence of rejection has decreased significantly at the UCLA program since the switch to tacrolimus and MMF, which “seems to have the best profile in terms of efficacy and lowest side effects,” he said. The major side effect differences with a tacrolimus-based regimen compared with cyclosporine are decreases in renal dysfunction, hyperlipidemia, and hypertension, which “all play a role in long-term outcome.”

Centers in the United States that still use cyclosporine-based regimens for heart transplant recipients will find it easier to switch now that heart transplantation is a primary indication, which will help insurance coverage, he said.

Prograf is marketed in Europe and Japan and is commercially available in about 70 countries, according to Astellas, the company that was created from the merger of Fujisawa Pharmaceutical Co. and Yamanouchi Pharmaceutical Co. last year. The U.S. approval pertains to both the capsule and intravenous formulations.

According to information provided by Astellas and the FDA, the March approval was based on two open-label, randomized studies comparing tacrolimus-based and cyclosporine-based immunosuppression in 645 primary orthotopic heart transplant recipients. In the European study, nearly 92% of patients and grafts had survived 18 months after transplantation, compared with nearly 90% of those who received cyclosporine-based regimens. In the U.S. study, 94% of patients and grafts survived at 12 months after transplantation, compared with 86% among those on the cyclosporine-based regimen.

Tacrolimus is associated with an increased risk of neurotoxicity, renal function impairment, infection, and posttransplant diabetes, and is associated with an increased risk of malignancies, “notably of nonmelanoma skin cancers,” the FDA statement said.

Another regimen for preventing heart transplant rejection—a combination of everolimus (a proliferation signal inhibitor) and cyclosporine—is under review at the FDA, but uncertainty over its adverse renal effects has held up approval in the United States. Data on the revised regimen from an ongoing European study are expected to be available by the end of this year.

ELSEVIER GLOBAL MEDICAL NEWS

The Food and Drug Administration has approved the immunosuppressant tacrolimus for preventing rejection in heart transplant recipients, on the basis of studies that found similar rates of patient and graft survival in patients on tacrolimus-based regimens and cyclosporine-based regimens.

Tacrolimus, marketed as Prograf by Astellas Pharma US, was previously approved for preventing rejection in kidney and liver transplant recipients and has been increasingly used off label for heart transplant recipients over the past several years.

During this time, “tacrolimus has been gaining favor as the first-line drug of choice,” said Dr. Jon Kobashigawa, medical director of the University of California, Los Angeles, heart transplant program, where a switch from a cyclosporine-based regimen to a tacrolimus-based regimen, usually with mycophenolate mofetil (MMF), was made about 5 years ago. After reports found it effective in reversing recurrent or refractory rejection, its use for primary prevention was studied in several trials, which demonstrated that a tacrolimus-based regimen was at least as effective as cyclosporine-based regimens, he said in an interview.

Two studies published in April in the American Journal of Transplantation demonstrated that the tacrolimus-based regimen was more effective in reducing rejection and had fewer side effects than did the cyclosporine-based regimen, said Dr. Kobashigawa, a principal investigator of one of these studies. He has received research grants and speaker honoraria from Astellas, and is on the company's scientific advisory board.

The incidence of rejection has decreased significantly at the UCLA program since the switch to tacrolimus and MMF, which “seems to have the best profile in terms of efficacy and lowest side effects,” he said. The major side effect differences with a tacrolimus-based regimen compared with cyclosporine are decreases in renal dysfunction, hyperlipidemia, and hypertension, which “all play a role in long-term outcome.”

Centers in the United States that still use cyclosporine-based regimens for heart transplant recipients will find it easier to switch now that heart transplantation is a primary indication, which will help insurance coverage, he said.

Prograf is marketed in Europe and Japan and is commercially available in about 70 countries, according to Astellas, the company that was created from the merger of Fujisawa Pharmaceutical Co. and Yamanouchi Pharmaceutical Co. last year. The U.S. approval pertains to both the capsule and intravenous formulations.

According to information provided by Astellas and the FDA, the March approval was based on two open-label, randomized studies comparing tacrolimus-based and cyclosporine-based immunosuppression in 645 primary orthotopic heart transplant recipients. In the European study, nearly 92% of patients and grafts had survived 18 months after transplantation, compared with nearly 90% of those who received cyclosporine-based regimens. In the U.S. study, 94% of patients and grafts survived at 12 months after transplantation, compared with 86% among those on the cyclosporine-based regimen.

Tacrolimus is associated with an increased risk of neurotoxicity, renal function impairment, infection, and posttransplant diabetes, and is associated with an increased risk of malignancies, “notably of nonmelanoma skin cancers,” the FDA statement said.

Another regimen for preventing heart transplant rejection—a combination of everolimus (a proliferation signal inhibitor) and cyclosporine—is under review at the FDA, but uncertainty over its adverse renal effects has held up approval in the United States. Data on the revised regimen from an ongoing European study are expected to be available by the end of this year.

ELSEVIER GLOBAL MEDICAL NEWS

The Food and Drug Administration has approved the immunosuppressant tacrolimus for preventing rejection in heart transplant recipients, on the basis of studies that found similar rates of patient and graft survival in patients on tacrolimus-based regimens and cyclosporine-based regimens.

Tacrolimus, marketed as Prograf by Astellas Pharma US, was previously approved for preventing rejection in kidney and liver transplant recipients and has been increasingly used off label for heart transplant recipients over the past several years.

During this time, “tacrolimus has been gaining favor as the first-line drug of choice,” said Dr. Jon Kobashigawa, medical director of the University of California, Los Angeles, heart transplant program, where a switch from a cyclosporine-based regimen to a tacrolimus-based regimen, usually with mycophenolate mofetil (MMF), was made about 5 years ago. After reports found it effective in reversing recurrent or refractory rejection, its use for primary prevention was studied in several trials, which demonstrated that a tacrolimus-based regimen was at least as effective as cyclosporine-based regimens, he said in an interview.

Two studies published in April in the American Journal of Transplantation demonstrated that the tacrolimus-based regimen was more effective in reducing rejection and had fewer side effects than did the cyclosporine-based regimen, said Dr. Kobashigawa, a principal investigator of one of these studies. He has received research grants and speaker honoraria from Astellas, and is on the company's scientific advisory board.

The incidence of rejection has decreased significantly at the UCLA program since the switch to tacrolimus and MMF, which “seems to have the best profile in terms of efficacy and lowest side effects,” he said. The major side effect differences with a tacrolimus-based regimen compared with cyclosporine are decreases in renal dysfunction, hyperlipidemia, and hypertension, which “all play a role in long-term outcome.”

Centers in the United States that still use cyclosporine-based regimens for heart transplant recipients will find it easier to switch now that heart transplantation is a primary indication, which will help insurance coverage, he said.

Prograf is marketed in Europe and Japan and is commercially available in about 70 countries, according to Astellas, the company that was created from the merger of Fujisawa Pharmaceutical Co. and Yamanouchi Pharmaceutical Co. last year. The U.S. approval pertains to both the capsule and intravenous formulations.

According to information provided by Astellas and the FDA, the March approval was based on two open-label, randomized studies comparing tacrolimus-based and cyclosporine-based immunosuppression in 645 primary orthotopic heart transplant recipients. In the European study, nearly 92% of patients and grafts had survived 18 months after transplantation, compared with nearly 90% of those who received cyclosporine-based regimens. In the U.S. study, 94% of patients and grafts survived at 12 months after transplantation, compared with 86% among those on the cyclosporine-based regimen.

Tacrolimus is associated with an increased risk of neurotoxicity, renal function impairment, infection, and posttransplant diabetes, and is associated with an increased risk of malignancies, “notably of nonmelanoma skin cancers,” the FDA statement said.

Another regimen for preventing heart transplant rejection—a combination of everolimus (a proliferation signal inhibitor) and cyclosporine—is under review at the FDA, but uncertainty over its adverse renal effects has held up approval in the United States. Data on the revised regimen from an ongoing European study are expected to be available by the end of this year.

ELSEVIER GLOBAL MEDICAL NEWS

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 in Buenos Aires.

These findings were based on a review of 58 patients aged 4–20 years—12 boys and 1 girl were younger than 10 years, and 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 the 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. Fully 93% had severe sustained hypertension, 7% had paroxysmal hypertension, and no patient 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 nearly 7% had normal urinary vanillylmandelic acid levels.

Among patients under age 20, 34% had bilateral adrenal pheochromocytoma and 22% had extraadrenal pheochromocytoma. Both were higher than they were in 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 20 years, compared with 22% of the older patients. Genetic testing, which was performed in familial cases, found some surprising differences, she noted.

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

In contrast, the most common mutation identified 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 in Buenos Aires.

These findings were based on a review of 58 patients aged 4–20 years—12 boys and 1 girl were younger than 10 years, and 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 the 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. Fully 93% had severe sustained hypertension, 7% had paroxysmal hypertension, and no patient 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 nearly 7% had normal urinary vanillylmandelic acid levels.

Among patients under age 20, 34% had bilateral adrenal pheochromocytoma and 22% had extraadrenal pheochromocytoma. Both were higher than they were in 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 20 years, compared with 22% of the older patients. Genetic testing, which was performed in familial cases, found some surprising differences, she noted.

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

In contrast, the most common mutation identified 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 in Buenos Aires.

These findings were based on a review of 58 patients aged 4–20 years—12 boys and 1 girl were younger than 10 years, and 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 the 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. Fully 93% had severe sustained hypertension, 7% had paroxysmal hypertension, and no patient 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 nearly 7% had normal urinary vanillylmandelic acid levels.

Among patients under age 20, 34% had bilateral adrenal pheochromocytoma and 22% had extraadrenal pheochromocytoma. Both were higher than they were in 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 20 years, compared with 22% of the older patients. Genetic testing, which was performed in familial cases, found some surprising differences, she noted.

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

In contrast, the most common mutation identified 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.