Elizabeth Mechcatie

GAITHERSBURG, MD. — Entecavir, an oral antiviral drug that has several advantages over currently available treatments for chronic hepatitis B, was approved recently by the Food and Drug Administration.

The approval came subsequent to the unanimous recommendation of all 18 members of the FDA's Antiviral Drugs Advisory Committee who agreed that the risk-benefit appraisal of entecavir supported its approval for treating chronic hepatitis B virus (HBV) infections in adults.

Despite concerns about a theoretical risk of malignancies, the panel voted in favor of approval, citing the very real risk of hepatocellular carcinoma associated with chronic HBV, safety and effectiveness data in 48-week trials of more than 1,000 patients who were either treatment naïve or refractory to lamivudine, and the lack of significant evidence of resistance to date.

There is “no question” that entecavir is very effective at reducing viral load, said Leonard Seeff, M.D., senior scientist for hepatitis research at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., a member of the panel. “We need other treatments, and this drug has advantages that others don't—namely, at least at this point, a lower rate of mutant strains developing and no nephrotoxicity.”

Kenneth Sherman, M.D., director of the hepatology and liver transplant medicine section at the University of Cincinnati, added that “as a hepatologist, I think this drug will add significantly to the tools we have available to treat patients with liver disease.”

The drug's manufacturer, Bristol-Myers Squibb (BMS), has agreed to conduct a large postmarketing study to determine whether the increased risk of lung tumors and other malignancies seen in rodents would occur in humans, and whether resistant strains would develop with a longer duration of treatment. The multinational trial would aim to enroll 12,500 patients worldwide, randomize them to entecavir or another HBV drug treatment, and follow them for malignancies and progression of liver disease for 5-8 years, according to BMS.

But the panel was concerned that the company could have problems enrolling enough patients in the trial, because entecavir was shown to be more effective than lamivudine in trials. Panel members also suggested that patients may have to be followed for longer periods.

BMS will market entecavir under the trade name Baraclude. Entecavir is a nucleoside analogue that is a potent, selective inhibitor of HBV replication. Currently available treatments for chronic HBV include interferon, approved in 1992, which is administered subcutaneously and is limited by its side effect profile. The first effective oral treatment for HBV, lamivudine (Epivir), a nucleoside analogue, was approved in 1998, but its usefulness is limited by the emergence of resistant strains after short durations of treatment.

Adefovir dipivoxil (Hepsera), a nucleotide analogue approved in 2002, is active against lamivudine-resistant virus, but can cause nephrotoxicity, which may limit its use in some populations.

At the meeting, BMS presented the results of clinical trials, including three phase III studies comparing entecavir with lamivudine in more than 1,500 patients with chronic HBV infections and active liver inflammation, including HBeAg-negative and HBeAg-positive patients who had not been treated with a nucleoside, and HBeAg-positive patients who were refractory to lamivudine. The patients in the trials did not have HIV.

In all three groups of patients, a significantly greater proportion of those treated with entecavir than of those treated with lamivudine met the primary end point, histologic improvement in liver biopsy after 48 weeks of treatment. Among the treatment-naïve patients, 70%-72% of those on entecavir met this end point vs. 61%-62% of those on lamivudine. Among lamivudine-refractory patients, 55% met this end point, vs. 28% of those who remained on lamivudine.

The safety profiles and malignancy rates were comparable in the entecavir and lamivudine-treated groups, according to the company.

Entecavir also has a favorable resistance profile compared with lamivudine, according to BMS:

Among entecavir-treated patients, viral resistance was not detected in any treatment-naïve patients at 48 weeks and was low among lamivudine-refractory patients (7%, leading to virologic rebound in 2%).

Hepatitis B affects about 400 million people worldwide, with about 1.25 million in the United States, and is the most common cause of cirrhosis and hepatocellular carcinoma, according to the FDA.

GAITHERSBURG, MD. — Entecavir, an oral antiviral drug that has several advantages over currently available treatments for chronic hepatitis B, was approved recently by the Food and Drug Administration.

The approval came subsequent to the unanimous recommendation of all 18 members of the FDA's Antiviral Drugs Advisory Committee who agreed that the risk-benefit appraisal of entecavir supported its approval for treating chronic hepatitis B virus (HBV) infections in adults.

Despite concerns about a theoretical risk of malignancies, the panel voted in favor of approval, citing the very real risk of hepatocellular carcinoma associated with chronic HBV, safety and effectiveness data in 48-week trials of more than 1,000 patients who were either treatment naïve or refractory to lamivudine, and the lack of significant evidence of resistance to date.

There is “no question” that entecavir is very effective at reducing viral load, said Leonard Seeff, M.D., senior scientist for hepatitis research at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., a member of the panel. “We need other treatments, and this drug has advantages that others don't—namely, at least at this point, a lower rate of mutant strains developing and no nephrotoxicity.”

Kenneth Sherman, M.D., director of the hepatology and liver transplant medicine section at the University of Cincinnati, added that “as a hepatologist, I think this drug will add significantly to the tools we have available to treat patients with liver disease.”

The drug's manufacturer, Bristol-Myers Squibb (BMS), has agreed to conduct a large postmarketing study to determine whether the increased risk of lung tumors and other malignancies seen in rodents would occur in humans, and whether resistant strains would develop with a longer duration of treatment. The multinational trial would aim to enroll 12,500 patients worldwide, randomize them to entecavir or another HBV drug treatment, and follow them for malignancies and progression of liver disease for 5-8 years, according to BMS.

But the panel was concerned that the company could have problems enrolling enough patients in the trial, because entecavir was shown to be more effective than lamivudine in trials. Panel members also suggested that patients may have to be followed for longer periods.

BMS will market entecavir under the trade name Baraclude. Entecavir is a nucleoside analogue that is a potent, selective inhibitor of HBV replication. Currently available treatments for chronic HBV include interferon, approved in 1992, which is administered subcutaneously and is limited by its side effect profile. The first effective oral treatment for HBV, lamivudine (Epivir), a nucleoside analogue, was approved in 1998, but its usefulness is limited by the emergence of resistant strains after short durations of treatment.

Adefovir dipivoxil (Hepsera), a nucleotide analogue approved in 2002, is active against lamivudine-resistant virus, but can cause nephrotoxicity, which may limit its use in some populations.

At the meeting, BMS presented the results of clinical trials, including three phase III studies comparing entecavir with lamivudine in more than 1,500 patients with chronic HBV infections and active liver inflammation, including HBeAg-negative and HBeAg-positive patients who had not been treated with a nucleoside, and HBeAg-positive patients who were refractory to lamivudine. The patients in the trials did not have HIV.

In all three groups of patients, a significantly greater proportion of those treated with entecavir than of those treated with lamivudine met the primary end point, histologic improvement in liver biopsy after 48 weeks of treatment. Among the treatment-naïve patients, 70%-72% of those on entecavir met this end point vs. 61%-62% of those on lamivudine. Among lamivudine-refractory patients, 55% met this end point, vs. 28% of those who remained on lamivudine.

The safety profiles and malignancy rates were comparable in the entecavir and lamivudine-treated groups, according to the company.

Entecavir also has a favorable resistance profile compared with lamivudine, according to BMS:

Among entecavir-treated patients, viral resistance was not detected in any treatment-naïve patients at 48 weeks and was low among lamivudine-refractory patients (7%, leading to virologic rebound in 2%).

Hepatitis B affects about 400 million people worldwide, with about 1.25 million in the United States, and is the most common cause of cirrhosis and hepatocellular carcinoma, according to the FDA.

GAITHERSBURG, MD. — Entecavir, an oral antiviral drug that has several advantages over currently available treatments for chronic hepatitis B, was approved recently by the Food and Drug Administration.

The approval came subsequent to the unanimous recommendation of all 18 members of the FDA's Antiviral Drugs Advisory Committee who agreed that the risk-benefit appraisal of entecavir supported its approval for treating chronic hepatitis B virus (HBV) infections in adults.

Despite concerns about a theoretical risk of malignancies, the panel voted in favor of approval, citing the very real risk of hepatocellular carcinoma associated with chronic HBV, safety and effectiveness data in 48-week trials of more than 1,000 patients who were either treatment naïve or refractory to lamivudine, and the lack of significant evidence of resistance to date.

There is “no question” that entecavir is very effective at reducing viral load, said Leonard Seeff, M.D., senior scientist for hepatitis research at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., a member of the panel. “We need other treatments, and this drug has advantages that others don't—namely, at least at this point, a lower rate of mutant strains developing and no nephrotoxicity.”

Kenneth Sherman, M.D., director of the hepatology and liver transplant medicine section at the University of Cincinnati, added that “as a hepatologist, I think this drug will add significantly to the tools we have available to treat patients with liver disease.”

The drug's manufacturer, Bristol-Myers Squibb (BMS), has agreed to conduct a large postmarketing study to determine whether the increased risk of lung tumors and other malignancies seen in rodents would occur in humans, and whether resistant strains would develop with a longer duration of treatment. The multinational trial would aim to enroll 12,500 patients worldwide, randomize them to entecavir or another HBV drug treatment, and follow them for malignancies and progression of liver disease for 5-8 years, according to BMS.

But the panel was concerned that the company could have problems enrolling enough patients in the trial, because entecavir was shown to be more effective than lamivudine in trials. Panel members also suggested that patients may have to be followed for longer periods.

BMS will market entecavir under the trade name Baraclude. Entecavir is a nucleoside analogue that is a potent, selective inhibitor of HBV replication. Currently available treatments for chronic HBV include interferon, approved in 1992, which is administered subcutaneously and is limited by its side effect profile. The first effective oral treatment for HBV, lamivudine (Epivir), a nucleoside analogue, was approved in 1998, but its usefulness is limited by the emergence of resistant strains after short durations of treatment.

Adefovir dipivoxil (Hepsera), a nucleotide analogue approved in 2002, is active against lamivudine-resistant virus, but can cause nephrotoxicity, which may limit its use in some populations.

At the meeting, BMS presented the results of clinical trials, including three phase III studies comparing entecavir with lamivudine in more than 1,500 patients with chronic HBV infections and active liver inflammation, including HBeAg-negative and HBeAg-positive patients who had not been treated with a nucleoside, and HBeAg-positive patients who were refractory to lamivudine. The patients in the trials did not have HIV.

In all three groups of patients, a significantly greater proportion of those treated with entecavir than of those treated with lamivudine met the primary end point, histologic improvement in liver biopsy after 48 weeks of treatment. Among the treatment-naïve patients, 70%-72% of those on entecavir met this end point vs. 61%-62% of those on lamivudine. Among lamivudine-refractory patients, 55% met this end point, vs. 28% of those who remained on lamivudine.

The safety profiles and malignancy rates were comparable in the entecavir and lamivudine-treated groups, according to the company.

Entecavir also has a favorable resistance profile compared with lamivudine, according to BMS:

Among entecavir-treated patients, viral resistance was not detected in any treatment-naïve patients at 48 weeks and was low among lamivudine-refractory patients (7%, leading to virologic rebound in 2%).

Hepatitis B affects about 400 million people worldwide, with about 1.25 million in the United States, and is the most common cause of cirrhosis and hepatocellular carcinoma, according to the FDA.

ROCKVILLE, MD. — The angiotensin receptor blocker candesartan should be approved as a treatment for heart failure in patients who are on an ACE inhibitor, a Food and Drug Administration advisory panel has recommended.

At a meeting of the FDA's cardiovascular and renal drugs advisory committee, all eight panel members backed approval of such an indication for candesartan on the basis of results of one of the three Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trials.

In CHARM-Added, candesartan (titrated to a target dose of 32 mg/day) was compared with placebo in 2,548 patients with New York Heart Association (NYHA) class II-IV heart failure and a left ventricular ejection fraction (LVEF) at or below 40% who were on an ACE inhibitor and standard therapy. The results showed that adding an ARB to standard treatment that included an ACE inhibitor added an incremental benefit in this population: The relative risk of cardiovascular mortality or heart failure (HF) hospitalization—the primary end point—was reduced by 15% among those on candesartan during a median follow-up of 41 months. The benefits were also seen in patients treated with β-blockers, which suggested there were no adverse interactions among β-blockers, candesartan, and ACE inhibitors, as noted in the Valsartan Heart Failure Trial (Val-HeFT), where the outcome for heart failure morbidity was worse among patients on an ACE inhibitor, β-blocker, and valsartan, according to the FDA.

The purpose of the meeting was to determine, according to the agenda, “whether CHARM-Added provides compelling evidence that candesartan should, under some circumstances, be recommended for use in patients on an ACE inhibitor.”

But a large portion of the meeting was spent discussing whether patients in the trial were on optimal ACE inhibitor doses and whether the same benefits might have been achieved by increasing the dose of the ACE inhibitor. What was missing in the study was a protocol-driven effort to ensure that investigators pushed ACE inhibitor doses to the best level possible, according to the agency.

Although panelists said a forced titration of ACE inhibitor therapy in the study protocol would have been ideal, they said they felt comfortable that the ACE inhibitor doses used fell into the ranges considered adequate or optimal. The “final doses of ACE inhibitor achieved were quite substantial” and in line with the doses seen in other trials of ACE inhibitor therapy, said Blasé Carabello, M.D., professor of medicine at Baylor University, Houston. In addition, an analysis of a subset of patients on high doses of ACE inhibitors “all go in the same direction” favoring the benefit.

The FDA usually follows the recommendations of its advisory panels, which are made up of outside experts. If approved, candesartan (marketed as Atacand by AstraZeneca Pharmaceuticals LP) will be the first ARB approved for use with an ACE inhibitor. Shortly before the panel meeting, the agency approved candesartan for patients with NYHA class II-IV heart failure, and an LVEF at or below 40%, who are not on an ACE inhibitor, to reduce the risk of death from cardiovascular causes and reduce HF hospitalization based on the CHARM-Alternative trial (FAMILY PRACTICE NEWS, Mar. 15, 2005, page 30).

James Hainer, M.D., senior director of clinical research at AstraZeneca, said that as expected, due to a greater degree of renin-angiotensin-aldosterone system inhibition, rates of hypotension, abnormal renal function, and hyperkalemia were greater with candesartan. However, these adverse events did not translate into any increases in all-cause hospitalization and/or mortality, sudden death, renal failure, or ventricular fibrillation. These risks will be addressed in warnings and precautions on the label, in recommendations for monitoring and reducing risk, and through interactions with major societies and guidelines committees.

Risks were “substantially” in favor of candesartan: An economic cost analysis found that over the course of the study, for every 1,000 patients treated with candesartan, there were 1,900 fewer days spent in the hospital for worsening heart failure, John McMurray, M.D., principal investigator of CHARM-Added and professor of medical cardiology, Western Infirmary, Glasgow, Scotland, told the panel.

ROCKVILLE, MD. — The angiotensin receptor blocker candesartan should be approved as a treatment for heart failure in patients who are on an ACE inhibitor, a Food and Drug Administration advisory panel has recommended.

At a meeting of the FDA's cardiovascular and renal drugs advisory committee, all eight panel members backed approval of such an indication for candesartan on the basis of results of one of the three Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trials.

In CHARM-Added, candesartan (titrated to a target dose of 32 mg/day) was compared with placebo in 2,548 patients with New York Heart Association (NYHA) class II-IV heart failure and a left ventricular ejection fraction (LVEF) at or below 40% who were on an ACE inhibitor and standard therapy. The results showed that adding an ARB to standard treatment that included an ACE inhibitor added an incremental benefit in this population: The relative risk of cardiovascular mortality or heart failure (HF) hospitalization—the primary end point—was reduced by 15% among those on candesartan during a median follow-up of 41 months. The benefits were also seen in patients treated with β-blockers, which suggested there were no adverse interactions among β-blockers, candesartan, and ACE inhibitors, as noted in the Valsartan Heart Failure Trial (Val-HeFT), where the outcome for heart failure morbidity was worse among patients on an ACE inhibitor, β-blocker, and valsartan, according to the FDA.

The purpose of the meeting was to determine, according to the agenda, “whether CHARM-Added provides compelling evidence that candesartan should, under some circumstances, be recommended for use in patients on an ACE inhibitor.”

But a large portion of the meeting was spent discussing whether patients in the trial were on optimal ACE inhibitor doses and whether the same benefits might have been achieved by increasing the dose of the ACE inhibitor. What was missing in the study was a protocol-driven effort to ensure that investigators pushed ACE inhibitor doses to the best level possible, according to the agency.

Although panelists said a forced titration of ACE inhibitor therapy in the study protocol would have been ideal, they said they felt comfortable that the ACE inhibitor doses used fell into the ranges considered adequate or optimal. The “final doses of ACE inhibitor achieved were quite substantial” and in line with the doses seen in other trials of ACE inhibitor therapy, said Blasé Carabello, M.D., professor of medicine at Baylor University, Houston. In addition, an analysis of a subset of patients on high doses of ACE inhibitors “all go in the same direction” favoring the benefit.

The FDA usually follows the recommendations of its advisory panels, which are made up of outside experts. If approved, candesartan (marketed as Atacand by AstraZeneca Pharmaceuticals LP) will be the first ARB approved for use with an ACE inhibitor. Shortly before the panel meeting, the agency approved candesartan for patients with NYHA class II-IV heart failure, and an LVEF at or below 40%, who are not on an ACE inhibitor, to reduce the risk of death from cardiovascular causes and reduce HF hospitalization based on the CHARM-Alternative trial (FAMILY PRACTICE NEWS, Mar. 15, 2005, page 30).

James Hainer, M.D., senior director of clinical research at AstraZeneca, said that as expected, due to a greater degree of renin-angiotensin-aldosterone system inhibition, rates of hypotension, abnormal renal function, and hyperkalemia were greater with candesartan. However, these adverse events did not translate into any increases in all-cause hospitalization and/or mortality, sudden death, renal failure, or ventricular fibrillation. These risks will be addressed in warnings and precautions on the label, in recommendations for monitoring and reducing risk, and through interactions with major societies and guidelines committees.

Risks were “substantially” in favor of candesartan: An economic cost analysis found that over the course of the study, for every 1,000 patients treated with candesartan, there were 1,900 fewer days spent in the hospital for worsening heart failure, John McMurray, M.D., principal investigator of CHARM-Added and professor of medical cardiology, Western Infirmary, Glasgow, Scotland, told the panel.

ROCKVILLE, MD. — The angiotensin receptor blocker candesartan should be approved as a treatment for heart failure in patients who are on an ACE inhibitor, a Food and Drug Administration advisory panel has recommended.

At a meeting of the FDA's cardiovascular and renal drugs advisory committee, all eight panel members backed approval of such an indication for candesartan on the basis of results of one of the three Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trials.

In CHARM-Added, candesartan (titrated to a target dose of 32 mg/day) was compared with placebo in 2,548 patients with New York Heart Association (NYHA) class II-IV heart failure and a left ventricular ejection fraction (LVEF) at or below 40% who were on an ACE inhibitor and standard therapy. The results showed that adding an ARB to standard treatment that included an ACE inhibitor added an incremental benefit in this population: The relative risk of cardiovascular mortality or heart failure (HF) hospitalization—the primary end point—was reduced by 15% among those on candesartan during a median follow-up of 41 months. The benefits were also seen in patients treated with β-blockers, which suggested there were no adverse interactions among β-blockers, candesartan, and ACE inhibitors, as noted in the Valsartan Heart Failure Trial (Val-HeFT), where the outcome for heart failure morbidity was worse among patients on an ACE inhibitor, β-blocker, and valsartan, according to the FDA.

The purpose of the meeting was to determine, according to the agenda, “whether CHARM-Added provides compelling evidence that candesartan should, under some circumstances, be recommended for use in patients on an ACE inhibitor.”

But a large portion of the meeting was spent discussing whether patients in the trial were on optimal ACE inhibitor doses and whether the same benefits might have been achieved by increasing the dose of the ACE inhibitor. What was missing in the study was a protocol-driven effort to ensure that investigators pushed ACE inhibitor doses to the best level possible, according to the agency.

Although panelists said a forced titration of ACE inhibitor therapy in the study protocol would have been ideal, they said they felt comfortable that the ACE inhibitor doses used fell into the ranges considered adequate or optimal. The “final doses of ACE inhibitor achieved were quite substantial” and in line with the doses seen in other trials of ACE inhibitor therapy, said Blasé Carabello, M.D., professor of medicine at Baylor University, Houston. In addition, an analysis of a subset of patients on high doses of ACE inhibitors “all go in the same direction” favoring the benefit.

The FDA usually follows the recommendations of its advisory panels, which are made up of outside experts. If approved, candesartan (marketed as Atacand by AstraZeneca Pharmaceuticals LP) will be the first ARB approved for use with an ACE inhibitor. Shortly before the panel meeting, the agency approved candesartan for patients with NYHA class II-IV heart failure, and an LVEF at or below 40%, who are not on an ACE inhibitor, to reduce the risk of death from cardiovascular causes and reduce HF hospitalization based on the CHARM-Alternative trial (FAMILY PRACTICE NEWS, Mar. 15, 2005, page 30).

James Hainer, M.D., senior director of clinical research at AstraZeneca, said that as expected, due to a greater degree of renin-angiotensin-aldosterone system inhibition, rates of hypotension, abnormal renal function, and hyperkalemia were greater with candesartan. However, these adverse events did not translate into any increases in all-cause hospitalization and/or mortality, sudden death, renal failure, or ventricular fibrillation. These risks will be addressed in warnings and precautions on the label, in recommendations for monitoring and reducing risk, and through interactions with major societies and guidelines committees.

Risks were “substantially” in favor of candesartan: An economic cost analysis found that over the course of the study, for every 1,000 patients treated with candesartan, there were 1,900 fewer days spent in the hospital for worsening heart failure, John McMurray, M.D., principal investigator of CHARM-Added and professor of medical cardiology, Western Infirmary, Glasgow, Scotland, told the panel.

GAITHERSBURG, MD. – A joint advisory panel of the Food and Drug Administration supported keeping all three approved selective cyclooxygenase-2 inhibitors on the U.S. market, with nearly unanimous support for celecoxib but far narrower votes for rofecoxib and valdecoxib, reflecting the strength of the data on the cardiovascular risks seen with those two drugs.

At the unprecedented 3-day joint meeting of the FDA's Arthritis Drugs and Drug Safety and Risk Management advisory committees, all 32 panel members agreed that, based on the available data, the three COX-2-selective NSAIDs approved in the United States significantly increase the risk of cardiovascular events, although to varying degrees, with the greatest risk evident for rofecoxib (Vioxx), voluntarily withdrawn from the U.S. market by Merck & Co. in September.

Alastair Wood, M.D., the panel chair, in summarizing the issues the panel faced before the questions were addressed, said there are now several randomized controlled trials showing significant cardiovascular risks associated with the three approved COX-2-selective NSAIDs–celecoxib (Celebrex), rofecoxib, and valdecoxib (Bextra)–which is a “far larger randomized safety signal than we've seen with any of the drugs that have been withdrawn [by the FDA] for safety reasons.”

The panel members agreed that celecoxib appeared to have the lowest risk and voted 31-1 that its overall risk-benefit profile supported continued marketing for the current indications in the United States.

For the other two COX-2 inhibitors, for which evidence of this risk was much stronger, the vote was divided, with rheumatologists tipping the balance toward support of the drugs' continued marketing. For rofecoxib, the panel voted 17-15 that the overall risk-benefit profile supported marketing the drug but recommended eliminating the highest dose (50 mg), restricting the dose to the lowest available dose (12.5 mg), and limiting rofecoxib to short-term use only.

For valdecoxib, the panel voted 17-13, with 2 abstentions, in favor of keeping it on the market, with a contraindication against use of the drug in cardiac surgery patients, based on study findings of substantially increased risk of coronary events in coronary artery bypass graft (CABG) patients.

Several panelists recommended against using valdecoxib for more than 6 months, because there are no data available on this drug for longer durations. And several said it should be considered a second-line drug.

The Food and Drug Administration usually follows the advice of its advisory panels. What the committees made clear was that these drugs “should not be as widely used” and should be used only in more carefully selected patients, in whom the benefits would outweigh the risks, said John Jenkins, M.D.

The FDA will review the panel's recommendations and expects to make final decisions about how to proceed within weeks, and will publicly announce the changes before they are implemented, said Dr. Jenkins, director of the FDA's office of new drugs, at a press briefing after the meeting.

Although the close votes for rofecoxib and valdecoxib are “challenging to interpret,” the agency will closely consider the comments of the panelists, he added.

In addition to withdrawing the drugs or adding a black box warning to the drugs' labels, the FDA's other options include changing the indications of the COX-2 selective NSAIDs to second-line drugs, adding contraindications in selected patient populations, and requiring a patient medication guide to be dispensed with all prescriptions.

Short of taking a drug off the market, some form of restricted-distribution program is another option, which is in place for drugs such as thalidomide and the antipsychotic clozapine (Clozaril). Although the FDA does not have the authority to ban pharmaceutical advertisements, a black box warning makes it difficult to advertise a drug directly to consumers because of requirements for disclosing information about a drug's negative effects.

During the press conference, Dr. Wood, the committee chair, who was among those voting against keeping rofecoxib and valdecoxib on the market, said that essentially, the panels provided a “clear ranking” of the drugs.

The uniform vote to keep celecoxib on the market and the split votes regarding rofecoxib and valdecoxib reflected the clear hazard seen with those two drugs.

Commenting on celecoxib specifically, Steven Abramson, M.D., professor of medicine and pathology and director of the department of rheumatology at New York University said, “While I tend to think there is a cardiovascular signal that is COX-2 dependent, this is the weakest.”

Cardiologist Steven Nissen, M.D., of the Cleveland Clinic Foundation, agreed, adding that the risk with celecoxib appeared to be dose dependent. Although there was no evidence of a cardiovascular risk signal associated with the 200-mg dose used in the vast majority of patients, the evidence of an increased risk came from the polyp-prevention trial, in which higher doses–400 mg/day and 800 mg/day–were used, he pointed out. The 800-mg dose was “very likely” to produce an excess risk, which was “probable” at the 400-mg dose, he said, advocating a black box warning of a dose-dependent increase in cardiovascular risk with this drug.

The data were considered more compelling for rofecoxib. Dr. Nissen, who voted against supporting the marketing of rofecoxib, except possibly under a compassionate use program, said the evidence of risk for rofecoxib raised more concerns.

He referred to blood pressure increases and a signal for heart failure “clearly” outside those of other drugs in the class demonstrated in the Adenomatous Polyp Prevention on Vioxx trial, at a daily dose of 25 mg–effects not seen at lower doses of celecoxib.

Compared with celecoxib and rofecoxib, there is much less information on valdecoxib, with data from only two trials available. Dr. Wood said he was uncertain whether the available data supported continued marketing of valdecoxib, which has a clear risk and no evidence of GI benefit. Referring to comments made at the meeting about patient choices, he said “it seems highly improbable” that valdecoxib is safer than celecoxib, given the size of the signal in the CABG study.

The panel agreed that some type of warning should be added to the labels of the more than 20 nonselective NSAIDs approved in the United States, for which safety has not been studied in long-term, large, placebo-controlled trials like those done for the COX-2-selective drugs.

However, several panelists recommended against using the same warning for all nonselective NSAIDs, given that naproxen as a comparator in trials seemed to do better than many of the other such drugs.

But there is still more to be learned about the traditional NSAIDs' safety, cautioned Dr. Wood, professor of medicine and pharmacology at Vanderbilt University, Nashville. However, the available data suggest that “naproxen is more beneficial than some of the others,” but it is associated with GI risks, so patients using naproxen could take a proton pump inhibitor (PPI).

There are not many data on naproxen given with a PPI, but there are “certainly data in other settings” supporting this approach, he noted.

At the meeting, Garret FitzGerald, M.D., professor of cardiovascular medicine at the University of Pennsylvania, a guest speaker for the FDA, said that given the pharmacoepidemiology and the body of evidence from clinical trials, “most rational people would accept a class-based mechanism” for these drugs.

He said that in five placebo-controlled trials with three structurally distinct COX-2 inhibitors, an increase in MI and/or stroke has been documented.

Dr. Steven Abramson (left) and Dr. Steven Nissen agree that among the COX-2s, celecoxib appears to have the weakest risk for cardiovascular events. James Reinaker

GAITHERSBURG, MD. – A joint advisory panel of the Food and Drug Administration supported keeping all three approved selective cyclooxygenase-2 inhibitors on the U.S. market, with nearly unanimous support for celecoxib but far narrower votes for rofecoxib and valdecoxib, reflecting the strength of the data on the cardiovascular risks seen with those two drugs.

At the unprecedented 3-day joint meeting of the FDA's Arthritis Drugs and Drug Safety and Risk Management advisory committees, all 32 panel members agreed that, based on the available data, the three COX-2-selective NSAIDs approved in the United States significantly increase the risk of cardiovascular events, although to varying degrees, with the greatest risk evident for rofecoxib (Vioxx), voluntarily withdrawn from the U.S. market by Merck & Co. in September.

Alastair Wood, M.D., the panel chair, in summarizing the issues the panel faced before the questions were addressed, said there are now several randomized controlled trials showing significant cardiovascular risks associated with the three approved COX-2-selective NSAIDs–celecoxib (Celebrex), rofecoxib, and valdecoxib (Bextra)–which is a “far larger randomized safety signal than we've seen with any of the drugs that have been withdrawn [by the FDA] for safety reasons.”

The panel members agreed that celecoxib appeared to have the lowest risk and voted 31-1 that its overall risk-benefit profile supported continued marketing for the current indications in the United States.

For the other two COX-2 inhibitors, for which evidence of this risk was much stronger, the vote was divided, with rheumatologists tipping the balance toward support of the drugs' continued marketing. For rofecoxib, the panel voted 17-15 that the overall risk-benefit profile supported marketing the drug but recommended eliminating the highest dose (50 mg), restricting the dose to the lowest available dose (12.5 mg), and limiting rofecoxib to short-term use only.

For valdecoxib, the panel voted 17-13, with 2 abstentions, in favor of keeping it on the market, with a contraindication against use of the drug in cardiac surgery patients, based on study findings of substantially increased risk of coronary events in coronary artery bypass graft (CABG) patients.

Several panelists recommended against using valdecoxib for more than 6 months, because there are no data available on this drug for longer durations. And several said it should be considered a second-line drug.

The Food and Drug Administration usually follows the advice of its advisory panels. What the committees made clear was that these drugs “should not be as widely used” and should be used only in more carefully selected patients, in whom the benefits would outweigh the risks, said John Jenkins, M.D.

The FDA will review the panel's recommendations and expects to make final decisions about how to proceed within weeks, and will publicly announce the changes before they are implemented, said Dr. Jenkins, director of the FDA's office of new drugs, at a press briefing after the meeting.

Although the close votes for rofecoxib and valdecoxib are “challenging to interpret,” the agency will closely consider the comments of the panelists, he added.

In addition to withdrawing the drugs or adding a black box warning to the drugs' labels, the FDA's other options include changing the indications of the COX-2 selective NSAIDs to second-line drugs, adding contraindications in selected patient populations, and requiring a patient medication guide to be dispensed with all prescriptions.

Short of taking a drug off the market, some form of restricted-distribution program is another option, which is in place for drugs such as thalidomide and the antipsychotic clozapine (Clozaril). Although the FDA does not have the authority to ban pharmaceutical advertisements, a black box warning makes it difficult to advertise a drug directly to consumers because of requirements for disclosing information about a drug's negative effects.

During the press conference, Dr. Wood, the committee chair, who was among those voting against keeping rofecoxib and valdecoxib on the market, said that essentially, the panels provided a “clear ranking” of the drugs.

The uniform vote to keep celecoxib on the market and the split votes regarding rofecoxib and valdecoxib reflected the clear hazard seen with those two drugs.

Commenting on celecoxib specifically, Steven Abramson, M.D., professor of medicine and pathology and director of the department of rheumatology at New York University said, “While I tend to think there is a cardiovascular signal that is COX-2 dependent, this is the weakest.”

Cardiologist Steven Nissen, M.D., of the Cleveland Clinic Foundation, agreed, adding that the risk with celecoxib appeared to be dose dependent. Although there was no evidence of a cardiovascular risk signal associated with the 200-mg dose used in the vast majority of patients, the evidence of an increased risk came from the polyp-prevention trial, in which higher doses–400 mg/day and 800 mg/day–were used, he pointed out. The 800-mg dose was “very likely” to produce an excess risk, which was “probable” at the 400-mg dose, he said, advocating a black box warning of a dose-dependent increase in cardiovascular risk with this drug.

The data were considered more compelling for rofecoxib. Dr. Nissen, who voted against supporting the marketing of rofecoxib, except possibly under a compassionate use program, said the evidence of risk for rofecoxib raised more concerns.

He referred to blood pressure increases and a signal for heart failure “clearly” outside those of other drugs in the class demonstrated in the Adenomatous Polyp Prevention on Vioxx trial, at a daily dose of 25 mg–effects not seen at lower doses of celecoxib.

Compared with celecoxib and rofecoxib, there is much less information on valdecoxib, with data from only two trials available. Dr. Wood said he was uncertain whether the available data supported continued marketing of valdecoxib, which has a clear risk and no evidence of GI benefit. Referring to comments made at the meeting about patient choices, he said “it seems highly improbable” that valdecoxib is safer than celecoxib, given the size of the signal in the CABG study.

The panel agreed that some type of warning should be added to the labels of the more than 20 nonselective NSAIDs approved in the United States, for which safety has not been studied in long-term, large, placebo-controlled trials like those done for the COX-2-selective drugs.

However, several panelists recommended against using the same warning for all nonselective NSAIDs, given that naproxen as a comparator in trials seemed to do better than many of the other such drugs.

But there is still more to be learned about the traditional NSAIDs' safety, cautioned Dr. Wood, professor of medicine and pharmacology at Vanderbilt University, Nashville. However, the available data suggest that “naproxen is more beneficial than some of the others,” but it is associated with GI risks, so patients using naproxen could take a proton pump inhibitor (PPI).

There are not many data on naproxen given with a PPI, but there are “certainly data in other settings” supporting this approach, he noted.

At the meeting, Garret FitzGerald, M.D., professor of cardiovascular medicine at the University of Pennsylvania, a guest speaker for the FDA, said that given the pharmacoepidemiology and the body of evidence from clinical trials, “most rational people would accept a class-based mechanism” for these drugs.

He said that in five placebo-controlled trials with three structurally distinct COX-2 inhibitors, an increase in MI and/or stroke has been documented.

Dr. Steven Abramson (left) and Dr. Steven Nissen agree that among the COX-2s, celecoxib appears to have the weakest risk for cardiovascular events. James Reinaker

GAITHERSBURG, MD. – A joint advisory panel of the Food and Drug Administration supported keeping all three approved selective cyclooxygenase-2 inhibitors on the U.S. market, with nearly unanimous support for celecoxib but far narrower votes for rofecoxib and valdecoxib, reflecting the strength of the data on the cardiovascular risks seen with those two drugs.

At the unprecedented 3-day joint meeting of the FDA's Arthritis Drugs and Drug Safety and Risk Management advisory committees, all 32 panel members agreed that, based on the available data, the three COX-2-selective NSAIDs approved in the United States significantly increase the risk of cardiovascular events, although to varying degrees, with the greatest risk evident for rofecoxib (Vioxx), voluntarily withdrawn from the U.S. market by Merck & Co. in September.

Alastair Wood, M.D., the panel chair, in summarizing the issues the panel faced before the questions were addressed, said there are now several randomized controlled trials showing significant cardiovascular risks associated with the three approved COX-2-selective NSAIDs–celecoxib (Celebrex), rofecoxib, and valdecoxib (Bextra)–which is a “far larger randomized safety signal than we've seen with any of the drugs that have been withdrawn [by the FDA] for safety reasons.”

The panel members agreed that celecoxib appeared to have the lowest risk and voted 31-1 that its overall risk-benefit profile supported continued marketing for the current indications in the United States.

For the other two COX-2 inhibitors, for which evidence of this risk was much stronger, the vote was divided, with rheumatologists tipping the balance toward support of the drugs' continued marketing. For rofecoxib, the panel voted 17-15 that the overall risk-benefit profile supported marketing the drug but recommended eliminating the highest dose (50 mg), restricting the dose to the lowest available dose (12.5 mg), and limiting rofecoxib to short-term use only.

For valdecoxib, the panel voted 17-13, with 2 abstentions, in favor of keeping it on the market, with a contraindication against use of the drug in cardiac surgery patients, based on study findings of substantially increased risk of coronary events in coronary artery bypass graft (CABG) patients.

Several panelists recommended against using valdecoxib for more than 6 months, because there are no data available on this drug for longer durations. And several said it should be considered a second-line drug.

The Food and Drug Administration usually follows the advice of its advisory panels. What the committees made clear was that these drugs “should not be as widely used” and should be used only in more carefully selected patients, in whom the benefits would outweigh the risks, said John Jenkins, M.D.

The FDA will review the panel's recommendations and expects to make final decisions about how to proceed within weeks, and will publicly announce the changes before they are implemented, said Dr. Jenkins, director of the FDA's office of new drugs, at a press briefing after the meeting.

Although the close votes for rofecoxib and valdecoxib are “challenging to interpret,” the agency will closely consider the comments of the panelists, he added.

In addition to withdrawing the drugs or adding a black box warning to the drugs' labels, the FDA's other options include changing the indications of the COX-2 selective NSAIDs to second-line drugs, adding contraindications in selected patient populations, and requiring a patient medication guide to be dispensed with all prescriptions.

Short of taking a drug off the market, some form of restricted-distribution program is another option, which is in place for drugs such as thalidomide and the antipsychotic clozapine (Clozaril). Although the FDA does not have the authority to ban pharmaceutical advertisements, a black box warning makes it difficult to advertise a drug directly to consumers because of requirements for disclosing information about a drug's negative effects.

During the press conference, Dr. Wood, the committee chair, who was among those voting against keeping rofecoxib and valdecoxib on the market, said that essentially, the panels provided a “clear ranking” of the drugs.

The uniform vote to keep celecoxib on the market and the split votes regarding rofecoxib and valdecoxib reflected the clear hazard seen with those two drugs.

Commenting on celecoxib specifically, Steven Abramson, M.D., professor of medicine and pathology and director of the department of rheumatology at New York University said, “While I tend to think there is a cardiovascular signal that is COX-2 dependent, this is the weakest.”

Cardiologist Steven Nissen, M.D., of the Cleveland Clinic Foundation, agreed, adding that the risk with celecoxib appeared to be dose dependent. Although there was no evidence of a cardiovascular risk signal associated with the 200-mg dose used in the vast majority of patients, the evidence of an increased risk came from the polyp-prevention trial, in which higher doses–400 mg/day and 800 mg/day–were used, he pointed out. The 800-mg dose was “very likely” to produce an excess risk, which was “probable” at the 400-mg dose, he said, advocating a black box warning of a dose-dependent increase in cardiovascular risk with this drug.

The data were considered more compelling for rofecoxib. Dr. Nissen, who voted against supporting the marketing of rofecoxib, except possibly under a compassionate use program, said the evidence of risk for rofecoxib raised more concerns.

He referred to blood pressure increases and a signal for heart failure “clearly” outside those of other drugs in the class demonstrated in the Adenomatous Polyp Prevention on Vioxx trial, at a daily dose of 25 mg–effects not seen at lower doses of celecoxib.

Compared with celecoxib and rofecoxib, there is much less information on valdecoxib, with data from only two trials available. Dr. Wood said he was uncertain whether the available data supported continued marketing of valdecoxib, which has a clear risk and no evidence of GI benefit. Referring to comments made at the meeting about patient choices, he said “it seems highly improbable” that valdecoxib is safer than celecoxib, given the size of the signal in the CABG study.

The panel agreed that some type of warning should be added to the labels of the more than 20 nonselective NSAIDs approved in the United States, for which safety has not been studied in long-term, large, placebo-controlled trials like those done for the COX-2-selective drugs.

However, several panelists recommended against using the same warning for all nonselective NSAIDs, given that naproxen as a comparator in trials seemed to do better than many of the other such drugs.

But there is still more to be learned about the traditional NSAIDs' safety, cautioned Dr. Wood, professor of medicine and pharmacology at Vanderbilt University, Nashville. However, the available data suggest that “naproxen is more beneficial than some of the others,” but it is associated with GI risks, so patients using naproxen could take a proton pump inhibitor (PPI).

There are not many data on naproxen given with a PPI, but there are “certainly data in other settings” supporting this approach, he noted.

At the meeting, Garret FitzGerald, M.D., professor of cardiovascular medicine at the University of Pennsylvania, a guest speaker for the FDA, said that given the pharmacoepidemiology and the body of evidence from clinical trials, “most rational people would accept a class-based mechanism” for these drugs.

He said that in five placebo-controlled trials with three structurally distinct COX-2 inhibitors, an increase in MI and/or stroke has been documented.

Dr. Steven Abramson (left) and Dr. Steven Nissen agree that among the COX-2s, celecoxib appears to have the weakest risk for cardiovascular events. James Reinaker

International reports of withdrawal symptoms in 93 newborns whose mothers had taken selective serotonin reuptake inhibitors during pregnancy raise concerns about a possible causal relationship between such symptoms and drugs in this class, particularly paroxetine, according to authors of a study that identified these cases.

Nearly two-thirds (64) of these cases were seen in babies whose mothers had taken paroxetine (Paxil), which the authors concluded should not be used in pregnancy, “or, if used, should be given at the lowest effective dose.”

The use of other SSRIs “should be carefully monitored and new cases promptly communicated to the pharmacovigilance systems,” wrote Emilio Sanz, M.D., professor of clinical pharmacology at the University of La Laguna (Spain), and associates (Lancet 2005;365:482–7).

When asked to comment on the study, two experts on drug therapy during pregnancy disagreed with the authors' conclusions, which they said fail to balance the risks and benefits of these drugs in pregnant women with depression.

Gideon Koren, M.D., director of the Motherisk Program, a teratogen information service at the Hospital for Sick Children, Toronto, said that while the identification of these cases in an international database was commendable, he took issue with the conclusion that paroxetine should not be used in pregnancy. This recommendation is not based on an appropriate risk-benefit analysis, he said, and it does not take into account the increased risk of maternal morbidity associated with untreated maternal depression—the strongest predictor of postpartum depression.

Moreover, the authors fail to take into account a study published last year, which found that in a large Swedish database, the association between paroxetine and these symptoms was no greater than with other SSRIs, added Dr. Koren, who said he has no financial ties to manufacturers of antidepressants.

He noted that neonatal withdrawal symptoms are self-limited and that the syndrome has “a very benign course,” which also was not discussed by the authors. He and his associates at Motherisk have conducted many prospective case-control studies on the effects of different drugs in pregnancy. One of the studies, published in 2002, found a significantly higher rate of neonatal withdrawal symptoms in newborns exposed to paroxetine in the third trimester, compared with unexposed controls.

Lee Cohen, M.D., director of the perinatal psychiatry program at Massachusetts General Hospital, Boston, emphasized that while an appropriate level of vigilance is warranted in neonates who have been exposed to SSRIs in the third trimester, the cases in the study represent spontaneous reports, not controlled data.

They are “not a clap of thunder” but represent another data set that is starting to suggest that there is some association between SSRI exposure and risk for perinatal syndrome, Dr. Cohen said in an interview.

What complicates the situation is that use of these drugs in the general population and in pregnant women is significant, but the incidence of these symptoms is probably extremely small. There are no controlled data available that can be used to reliably estimate the prevalence of these symptoms in pregnant women on antidepressants, added Dr. Cohen, who is a consultant to manufacturers of several antidepressants.

What concerns him most, Dr. Cohen said, is that the study could not only lead to a reduction in antidepressant use during the peripartum period, but could affect a woman's willingness to take medication she may need at other points during pregnancy. The study also could affect the clinicians' willingness to prescribe therapy when needed during pregnancy.

The study, published last month, involved a search for reports of cases in the WHO adverse drug reaction database, where spontaneous reports of suspected adverse drug reactions are sent from centers in 81 countries. The first case, which was associated with fluoxetine, was reported in 1995. As of November 2003, 93 suspected cases of SSRI-associated neonatal withdrawal syndrome had been reported. In 73 of those cases, no concomitant medications were reported or the concomitant medications were thought to be unrelated to the symptoms.

For 10 of the remaining 20 cases, an association with the SSRIs was considered “doubtful,” because of the concomitant use of medications that included antipsychotics or other drugs for which an association with neonatal withdrawal symptoms have not been clearly established. Another 10 were considered as “probably not” associated with SSRIs, because concomitant medications included drugs like opioids or tricyclics, according to the authors.

The most common neurological symptoms reported were nervousness, abnormal crying, tremors, and hypertonia. Other symptoms included digestive symptoms (vomiting, feeding disorders, or diarrhea), and respiratory symptoms (including two cases of respiratory depression). There were 13 cases of neonatal convulsions—11 listed as neonatal convulsions and 2 as grand mal convulsions.

Of the 93 cases, 64 were associated with exposure to paroxetine, followed by 14 associated with fluoxetine (Prozac), 9 with sertraline (Zoloft), and 7 with citalopram (Celexa). Information on doses and duration of treatment during pregnancy were reported in a minority of cases.

A spokesperson for Paxil manufacturer GlaxoSmithKline said the company had no statement on the Lancet report but pointed out that the FDA required this label change for all SSRIs and selective norepinephrine reuptake inhibitors (SNRIs).

International reports of withdrawal symptoms in 93 newborns whose mothers had taken selective serotonin reuptake inhibitors during pregnancy raise concerns about a possible causal relationship between such symptoms and drugs in this class, particularly paroxetine, according to authors of a study that identified these cases.

Nearly two-thirds (64) of these cases were seen in babies whose mothers had taken paroxetine (Paxil), which the authors concluded should not be used in pregnancy, “or, if used, should be given at the lowest effective dose.”

The use of other SSRIs “should be carefully monitored and new cases promptly communicated to the pharmacovigilance systems,” wrote Emilio Sanz, M.D., professor of clinical pharmacology at the University of La Laguna (Spain), and associates (Lancet 2005;365:482–7).

When asked to comment on the study, two experts on drug therapy during pregnancy disagreed with the authors' conclusions, which they said fail to balance the risks and benefits of these drugs in pregnant women with depression.

Gideon Koren, M.D., director of the Motherisk Program, a teratogen information service at the Hospital for Sick Children, Toronto, said that while the identification of these cases in an international database was commendable, he took issue with the conclusion that paroxetine should not be used in pregnancy. This recommendation is not based on an appropriate risk-benefit analysis, he said, and it does not take into account the increased risk of maternal morbidity associated with untreated maternal depression—the strongest predictor of postpartum depression.

Moreover, the authors fail to take into account a study published last year, which found that in a large Swedish database, the association between paroxetine and these symptoms was no greater than with other SSRIs, added Dr. Koren, who said he has no financial ties to manufacturers of antidepressants.

He noted that neonatal withdrawal symptoms are self-limited and that the syndrome has “a very benign course,” which also was not discussed by the authors. He and his associates at Motherisk have conducted many prospective case-control studies on the effects of different drugs in pregnancy. One of the studies, published in 2002, found a significantly higher rate of neonatal withdrawal symptoms in newborns exposed to paroxetine in the third trimester, compared with unexposed controls.

Lee Cohen, M.D., director of the perinatal psychiatry program at Massachusetts General Hospital, Boston, emphasized that while an appropriate level of vigilance is warranted in neonates who have been exposed to SSRIs in the third trimester, the cases in the study represent spontaneous reports, not controlled data.

They are “not a clap of thunder” but represent another data set that is starting to suggest that there is some association between SSRI exposure and risk for perinatal syndrome, Dr. Cohen said in an interview.

What complicates the situation is that use of these drugs in the general population and in pregnant women is significant, but the incidence of these symptoms is probably extremely small. There are no controlled data available that can be used to reliably estimate the prevalence of these symptoms in pregnant women on antidepressants, added Dr. Cohen, who is a consultant to manufacturers of several antidepressants.

What concerns him most, Dr. Cohen said, is that the study could not only lead to a reduction in antidepressant use during the peripartum period, but could affect a woman's willingness to take medication she may need at other points during pregnancy. The study also could affect the clinicians' willingness to prescribe therapy when needed during pregnancy.

The study, published last month, involved a search for reports of cases in the WHO adverse drug reaction database, where spontaneous reports of suspected adverse drug reactions are sent from centers in 81 countries. The first case, which was associated with fluoxetine, was reported in 1995. As of November 2003, 93 suspected cases of SSRI-associated neonatal withdrawal syndrome had been reported. In 73 of those cases, no concomitant medications were reported or the concomitant medications were thought to be unrelated to the symptoms.

For 10 of the remaining 20 cases, an association with the SSRIs was considered “doubtful,” because of the concomitant use of medications that included antipsychotics or other drugs for which an association with neonatal withdrawal symptoms have not been clearly established. Another 10 were considered as “probably not” associated with SSRIs, because concomitant medications included drugs like opioids or tricyclics, according to the authors.

The most common neurological symptoms reported were nervousness, abnormal crying, tremors, and hypertonia. Other symptoms included digestive symptoms (vomiting, feeding disorders, or diarrhea), and respiratory symptoms (including two cases of respiratory depression). There were 13 cases of neonatal convulsions—11 listed as neonatal convulsions and 2 as grand mal convulsions.

Of the 93 cases, 64 were associated with exposure to paroxetine, followed by 14 associated with fluoxetine (Prozac), 9 with sertraline (Zoloft), and 7 with citalopram (Celexa). Information on doses and duration of treatment during pregnancy were reported in a minority of cases.

A spokesperson for Paxil manufacturer GlaxoSmithKline said the company had no statement on the Lancet report but pointed out that the FDA required this label change for all SSRIs and selective norepinephrine reuptake inhibitors (SNRIs).

International reports of withdrawal symptoms in 93 newborns whose mothers had taken selective serotonin reuptake inhibitors during pregnancy raise concerns about a possible causal relationship between such symptoms and drugs in this class, particularly paroxetine, according to authors of a study that identified these cases.

Nearly two-thirds (64) of these cases were seen in babies whose mothers had taken paroxetine (Paxil), which the authors concluded should not be used in pregnancy, “or, if used, should be given at the lowest effective dose.”

The use of other SSRIs “should be carefully monitored and new cases promptly communicated to the pharmacovigilance systems,” wrote Emilio Sanz, M.D., professor of clinical pharmacology at the University of La Laguna (Spain), and associates (Lancet 2005;365:482–7).

When asked to comment on the study, two experts on drug therapy during pregnancy disagreed with the authors' conclusions, which they said fail to balance the risks and benefits of these drugs in pregnant women with depression.

Gideon Koren, M.D., director of the Motherisk Program, a teratogen information service at the Hospital for Sick Children, Toronto, said that while the identification of these cases in an international database was commendable, he took issue with the conclusion that paroxetine should not be used in pregnancy. This recommendation is not based on an appropriate risk-benefit analysis, he said, and it does not take into account the increased risk of maternal morbidity associated with untreated maternal depression—the strongest predictor of postpartum depression.

Moreover, the authors fail to take into account a study published last year, which found that in a large Swedish database, the association between paroxetine and these symptoms was no greater than with other SSRIs, added Dr. Koren, who said he has no financial ties to manufacturers of antidepressants.

He noted that neonatal withdrawal symptoms are self-limited and that the syndrome has “a very benign course,” which also was not discussed by the authors. He and his associates at Motherisk have conducted many prospective case-control studies on the effects of different drugs in pregnancy. One of the studies, published in 2002, found a significantly higher rate of neonatal withdrawal symptoms in newborns exposed to paroxetine in the third trimester, compared with unexposed controls.

Lee Cohen, M.D., director of the perinatal psychiatry program at Massachusetts General Hospital, Boston, emphasized that while an appropriate level of vigilance is warranted in neonates who have been exposed to SSRIs in the third trimester, the cases in the study represent spontaneous reports, not controlled data.

They are “not a clap of thunder” but represent another data set that is starting to suggest that there is some association between SSRI exposure and risk for perinatal syndrome, Dr. Cohen said in an interview.

What complicates the situation is that use of these drugs in the general population and in pregnant women is significant, but the incidence of these symptoms is probably extremely small. There are no controlled data available that can be used to reliably estimate the prevalence of these symptoms in pregnant women on antidepressants, added Dr. Cohen, who is a consultant to manufacturers of several antidepressants.

What concerns him most, Dr. Cohen said, is that the study could not only lead to a reduction in antidepressant use during the peripartum period, but could affect a woman's willingness to take medication she may need at other points during pregnancy. The study also could affect the clinicians' willingness to prescribe therapy when needed during pregnancy.

The study, published last month, involved a search for reports of cases in the WHO adverse drug reaction database, where spontaneous reports of suspected adverse drug reactions are sent from centers in 81 countries. The first case, which was associated with fluoxetine, was reported in 1995. As of November 2003, 93 suspected cases of SSRI-associated neonatal withdrawal syndrome had been reported. In 73 of those cases, no concomitant medications were reported or the concomitant medications were thought to be unrelated to the symptoms.

For 10 of the remaining 20 cases, an association with the SSRIs was considered “doubtful,” because of the concomitant use of medications that included antipsychotics or other drugs for which an association with neonatal withdrawal symptoms have not been clearly established. Another 10 were considered as “probably not” associated with SSRIs, because concomitant medications included drugs like opioids or tricyclics, according to the authors.

The most common neurological symptoms reported were nervousness, abnormal crying, tremors, and hypertonia. Other symptoms included digestive symptoms (vomiting, feeding disorders, or diarrhea), and respiratory symptoms (including two cases of respiratory depression). There were 13 cases of neonatal convulsions—11 listed as neonatal convulsions and 2 as grand mal convulsions.

Of the 93 cases, 64 were associated with exposure to paroxetine, followed by 14 associated with fluoxetine (Prozac), 9 with sertraline (Zoloft), and 7 with citalopram (Celexa). Information on doses and duration of treatment during pregnancy were reported in a minority of cases.

A spokesperson for Paxil manufacturer GlaxoSmithKline said the company had no statement on the Lancet report but pointed out that the FDA required this label change for all SSRIs and selective norepinephrine reuptake inhibitors (SNRIs).

Vaccinia Immune Globulin Intravenous

(DynPort Vaccine Co.)

An immunoglobulin containing antivaccinia antibody for the treatment and/or modification of serious complications of smallpox vaccination, including eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, and vaccinia infections in people who have skin conditions, such as burns, impetigo, or varicella zoster.

▸ Recommended Dosage: 2 mL/kg administered in an intravenous infusion.

▸ Special Considerations: Adverse effects in two studies of 111 healthy volunteers included headaches, hives, and other types of rashes, but were mild to moderate; overall, vaccinia immune globulin intravenous (VIGIV) was well tolerated.

▸ Comment: Approval of VIGIV—derived from pooled plasma of donors who received booster doses of the approved smallpox vaccine—was based on these studies. In one, serum antibody levels achieved were comparable with those expected with a previously approved intramuscular vaccinia immunoglobulin, but no controlled studies have shown a clinical benefit, such as a reduction in mortality.

The Food and Drug Administration approved VIGIV with the condition that postmarketing studies be conducted, including assessing clinical benefits, such as increased survival in patients with progressive vaccinia and eczema vaccinatum. In a statement, the FDA said the product “may help minimize” the risks of the smallpox vaccine, when used in cases where the vaccine's benefits are thought to outweigh its risks, citing the example of responders to a bioterrorist attack.

Atacand

(candesartan, AstraZeneca)

An angiotensin receptor blocker (ARB) for treating patients with heart failure (NYHA class II-IV and an ejection fraction of 40% or less), to reduce the risk of death from cardiovascular causes and reduce hospitalizations for heart failure. Previously approved for hypertension. The second ARB approved for heart failure (HF); the first was Diovan (valsartan), approved in 2002 for a narrower indication, NYHA class II-IV heart failure in people who cannot tolerate ACE inhibitors. Being reviewed for use with an ACE inhibitor in treating HF, as backed by an FDA advisory panel last month.

▸ Recommended Dosage: Starting at 4 mg/day, with a target dose of 32 mg once daily, achieved by doubling the dose approximately every 2 weeks, as tolerated.

▸ Special Considerations: In the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program, three trials comparing Atacand with placebo in HF populations, 4% of those on Atacand had to stop use of the drug because of hypotension, vs. 2% of those on placebo. Hyperkalemia leading to discontinuation occurred in 2.4% of those on Atacand and 0.6% of those on placebo. Patients must be monitored closely during titration because some develop renal insufficiency, hyperkalemia, or hypotension—side effects expected with any drug that affects the renal angiotensin system, said Christopher Granger, M.D., director of the cardiac care unit at Duke University, Durham, N.C.

▸ Comment: This approval reflects findings of one of the three CHARM trials, CHARM-Alternative, which enrolled 2,028 patients with symptomatic heart failure and a left ventricular ejection fraction of 40% or less, who were on standard HF treatments but were intolerant of ACE inhibitors. After a median follow-up of 34 months, the risk of cardiovascular death or HF hospitalization was reduced by 23% in those on Atacand, compared with those on placebo, a highly significant effect.

Supporting the approval were results of CHARM-Added, of more than 2,500 patients with NYHA class II-IV heart failure and ejection fractions of 40% or less, and on an ACE inhibitor. Adding Atacand to standard treatment, including a β-blocker, cut cardiovascular mortality by 15%, compared with placebo. The key findings of the CHARM program were that in patients with left ventricular dysfunction, Atacand cut cardiovascular mortality and hospitalization for HF, “and made people feel better,” said Dr. Granger, who was on the executive committee for CHARM. He served as a consultant to AstraZeneca at the meeting of the FDA's Cardiovascular and Renal Drugs Advisory Committee, which unanimously recommended approval of Atacand for use in patients on an ACE inhibitor.

Atacand will be an important new tool for treating heart failure. The challenge for clinicians “is to successfully integrate a fairly complex set of medications for patients with chronic heart failure, including careful titration and monitoring to assure that we achieve the benefits that have been seen in trials, and that we do it safely.”

Vaccinia Immune Globulin Intravenous

(DynPort Vaccine Co.)

An immunoglobulin containing antivaccinia antibody for the treatment and/or modification of serious complications of smallpox vaccination, including eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, and vaccinia infections in people who have skin conditions, such as burns, impetigo, or varicella zoster.

▸ Recommended Dosage: 2 mL/kg administered in an intravenous infusion.

▸ Special Considerations: Adverse effects in two studies of 111 healthy volunteers included headaches, hives, and other types of rashes, but were mild to moderate; overall, vaccinia immune globulin intravenous (VIGIV) was well tolerated.

▸ Comment: Approval of VIGIV—derived from pooled plasma of donors who received booster doses of the approved smallpox vaccine—was based on these studies. In one, serum antibody levels achieved were comparable with those expected with a previously approved intramuscular vaccinia immunoglobulin, but no controlled studies have shown a clinical benefit, such as a reduction in mortality.

The Food and Drug Administration approved VIGIV with the condition that postmarketing studies be conducted, including assessing clinical benefits, such as increased survival in patients with progressive vaccinia and eczema vaccinatum. In a statement, the FDA said the product “may help minimize” the risks of the smallpox vaccine, when used in cases where the vaccine's benefits are thought to outweigh its risks, citing the example of responders to a bioterrorist attack.

Atacand

(candesartan, AstraZeneca)

An angiotensin receptor blocker (ARB) for treating patients with heart failure (NYHA class II-IV and an ejection fraction of 40% or less), to reduce the risk of death from cardiovascular causes and reduce hospitalizations for heart failure. Previously approved for hypertension. The second ARB approved for heart failure (HF); the first was Diovan (valsartan), approved in 2002 for a narrower indication, NYHA class II-IV heart failure in people who cannot tolerate ACE inhibitors. Being reviewed for use with an ACE inhibitor in treating HF, as backed by an FDA advisory panel last month.

▸ Recommended Dosage: Starting at 4 mg/day, with a target dose of 32 mg once daily, achieved by doubling the dose approximately every 2 weeks, as tolerated.

▸ Special Considerations: In the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program, three trials comparing Atacand with placebo in HF populations, 4% of those on Atacand had to stop use of the drug because of hypotension, vs. 2% of those on placebo. Hyperkalemia leading to discontinuation occurred in 2.4% of those on Atacand and 0.6% of those on placebo. Patients must be monitored closely during titration because some develop renal insufficiency, hyperkalemia, or hypotension—side effects expected with any drug that affects the renal angiotensin system, said Christopher Granger, M.D., director of the cardiac care unit at Duke University, Durham, N.C.

▸ Comment: This approval reflects findings of one of the three CHARM trials, CHARM-Alternative, which enrolled 2,028 patients with symptomatic heart failure and a left ventricular ejection fraction of 40% or less, who were on standard HF treatments but were intolerant of ACE inhibitors. After a median follow-up of 34 months, the risk of cardiovascular death or HF hospitalization was reduced by 23% in those on Atacand, compared with those on placebo, a highly significant effect.

Supporting the approval were results of CHARM-Added, of more than 2,500 patients with NYHA class II-IV heart failure and ejection fractions of 40% or less, and on an ACE inhibitor. Adding Atacand to standard treatment, including a β-blocker, cut cardiovascular mortality by 15%, compared with placebo. The key findings of the CHARM program were that in patients with left ventricular dysfunction, Atacand cut cardiovascular mortality and hospitalization for HF, “and made people feel better,” said Dr. Granger, who was on the executive committee for CHARM. He served as a consultant to AstraZeneca at the meeting of the FDA's Cardiovascular and Renal Drugs Advisory Committee, which unanimously recommended approval of Atacand for use in patients on an ACE inhibitor.

Atacand will be an important new tool for treating heart failure. The challenge for clinicians “is to successfully integrate a fairly complex set of medications for patients with chronic heart failure, including careful titration and monitoring to assure that we achieve the benefits that have been seen in trials, and that we do it safely.”

Vaccinia Immune Globulin Intravenous

(DynPort Vaccine Co.)

An immunoglobulin containing antivaccinia antibody for the treatment and/or modification of serious complications of smallpox vaccination, including eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, and vaccinia infections in people who have skin conditions, such as burns, impetigo, or varicella zoster.

▸ Recommended Dosage: 2 mL/kg administered in an intravenous infusion.

▸ Special Considerations: Adverse effects in two studies of 111 healthy volunteers included headaches, hives, and other types of rashes, but were mild to moderate; overall, vaccinia immune globulin intravenous (VIGIV) was well tolerated.

▸ Comment: Approval of VIGIV—derived from pooled plasma of donors who received booster doses of the approved smallpox vaccine—was based on these studies. In one, serum antibody levels achieved were comparable with those expected with a previously approved intramuscular vaccinia immunoglobulin, but no controlled studies have shown a clinical benefit, such as a reduction in mortality.

The Food and Drug Administration approved VIGIV with the condition that postmarketing studies be conducted, including assessing clinical benefits, such as increased survival in patients with progressive vaccinia and eczema vaccinatum. In a statement, the FDA said the product “may help minimize” the risks of the smallpox vaccine, when used in cases where the vaccine's benefits are thought to outweigh its risks, citing the example of responders to a bioterrorist attack.

Atacand

(candesartan, AstraZeneca)

An angiotensin receptor blocker (ARB) for treating patients with heart failure (NYHA class II-IV and an ejection fraction of 40% or less), to reduce the risk of death from cardiovascular causes and reduce hospitalizations for heart failure. Previously approved for hypertension. The second ARB approved for heart failure (HF); the first was Diovan (valsartan), approved in 2002 for a narrower indication, NYHA class II-IV heart failure in people who cannot tolerate ACE inhibitors. Being reviewed for use with an ACE inhibitor in treating HF, as backed by an FDA advisory panel last month.

▸ Recommended Dosage: Starting at 4 mg/day, with a target dose of 32 mg once daily, achieved by doubling the dose approximately every 2 weeks, as tolerated.

▸ Special Considerations: In the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program, three trials comparing Atacand with placebo in HF populations, 4% of those on Atacand had to stop use of the drug because of hypotension, vs. 2% of those on placebo. Hyperkalemia leading to discontinuation occurred in 2.4% of those on Atacand and 0.6% of those on placebo. Patients must be monitored closely during titration because some develop renal insufficiency, hyperkalemia, or hypotension—side effects expected with any drug that affects the renal angiotensin system, said Christopher Granger, M.D., director of the cardiac care unit at Duke University, Durham, N.C.

▸ Comment: This approval reflects findings of one of the three CHARM trials, CHARM-Alternative, which enrolled 2,028 patients with symptomatic heart failure and a left ventricular ejection fraction of 40% or less, who were on standard HF treatments but were intolerant of ACE inhibitors. After a median follow-up of 34 months, the risk of cardiovascular death or HF hospitalization was reduced by 23% in those on Atacand, compared with those on placebo, a highly significant effect.

Supporting the approval were results of CHARM-Added, of more than 2,500 patients with NYHA class II-IV heart failure and ejection fractions of 40% or less, and on an ACE inhibitor. Adding Atacand to standard treatment, including a β-blocker, cut cardiovascular mortality by 15%, compared with placebo. The key findings of the CHARM program were that in patients with left ventricular dysfunction, Atacand cut cardiovascular mortality and hospitalization for HF, “and made people feel better,” said Dr. Granger, who was on the executive committee for CHARM. He served as a consultant to AstraZeneca at the meeting of the FDA's Cardiovascular and Renal Drugs Advisory Committee, which unanimously recommended approval of Atacand for use in patients on an ACE inhibitor.

Atacand will be an important new tool for treating heart failure. The challenge for clinicians “is to successfully integrate a fairly complex set of medications for patients with chronic heart failure, including careful titration and monitoring to assure that we achieve the benefits that have been seen in trials, and that we do it safely.”

A study of 41 people aged 22-66 years found evidence of small-bowel injury on capsule endoscopy in 71% of those taking a nonsteroidal anti-inflammatory drug for at least 3 months.

By comparison, 10% of control patients not taking NSAIDs had such injuries—a highly significant difference. While it's known that NSAIDs are associated with small-intestine injuries and may be the cause of unexplained hypoalbuminemia or anemia, the extent of the small-intestine damage had previously not been well characterized, according to the lead investigator, David Y. Graham, M.D., chief of gastroenterology and professor of medicine at Baylor College of Medicine in Houston.

The study does not have clinical implications for managing patients currently, but will serve as a basis of future studies, he said in an interview. The next step is to investigate how these findings correlate with anemia or protein loss and whether NSAIDs vary in their ability to induce these effects, he added.

Patients in the study had various arthritides, but were generally healthy and did not have anemia or hypoalbuminemia. Of the 21 patients on NSAIDs, 5 had major damage defined as having more than four erosions or large ulcers. None of the 20 control patients had major damage (Clin. Gastroenterol. Hepatol. 2005;3:55-9).

The ulcers were more common than anticipated, said Dr. Graham, noting that previous estimates of small-intestine damage associated with NSAIDs have come from autopsy studies, which found a rate of 5%-8%.

A study of 41 people aged 22-66 years found evidence of small-bowel injury on capsule endoscopy in 71% of those taking a nonsteroidal anti-inflammatory drug for at least 3 months.

By comparison, 10% of control patients not taking NSAIDs had such injuries—a highly significant difference. While it's known that NSAIDs are associated with small-intestine injuries and may be the cause of unexplained hypoalbuminemia or anemia, the extent of the small-intestine damage had previously not been well characterized, according to the lead investigator, David Y. Graham, M.D., chief of gastroenterology and professor of medicine at Baylor College of Medicine in Houston.

The study does not have clinical implications for managing patients currently, but will serve as a basis of future studies, he said in an interview. The next step is to investigate how these findings correlate with anemia or protein loss and whether NSAIDs vary in their ability to induce these effects, he added.

Patients in the study had various arthritides, but were generally healthy and did not have anemia or hypoalbuminemia. Of the 21 patients on NSAIDs, 5 had major damage defined as having more than four erosions or large ulcers. None of the 20 control patients had major damage (Clin. Gastroenterol. Hepatol. 2005;3:55-9).

The ulcers were more common than anticipated, said Dr. Graham, noting that previous estimates of small-intestine damage associated with NSAIDs have come from autopsy studies, which found a rate of 5%-8%.

A study of 41 people aged 22-66 years found evidence of small-bowel injury on capsule endoscopy in 71% of those taking a nonsteroidal anti-inflammatory drug for at least 3 months.

By comparison, 10% of control patients not taking NSAIDs had such injuries—a highly significant difference. While it's known that NSAIDs are associated with small-intestine injuries and may be the cause of unexplained hypoalbuminemia or anemia, the extent of the small-intestine damage had previously not been well characterized, according to the lead investigator, David Y. Graham, M.D., chief of gastroenterology and professor of medicine at Baylor College of Medicine in Houston.

The study does not have clinical implications for managing patients currently, but will serve as a basis of future studies, he said in an interview. The next step is to investigate how these findings correlate with anemia or protein loss and whether NSAIDs vary in their ability to induce these effects, he added.

Patients in the study had various arthritides, but were generally healthy and did not have anemia or hypoalbuminemia. Of the 21 patients on NSAIDs, 5 had major damage defined as having more than four erosions or large ulcers. None of the 20 control patients had major damage (Clin. Gastroenterol. Hepatol. 2005;3:55-9).

The ulcers were more common than anticipated, said Dr. Graham, noting that previous estimates of small-intestine damage associated with NSAIDs have come from autopsy studies, which found a rate of 5%-8%.

WASHINGTON — Primary care physicians are less likely than specialists to initiate a work-up for secondary causes of bone loss in patients with scans indicating low bone density, despite a recommendation to do so.

That finding emerged from a study presented in poster form during the annual meeting of the North American Menopause Society.

Some patients with scans indicating osteoporosis were premenopausal women who started treatment with a bisphosphonate after their physicians received the scan results. Eventually, however, these patients were diagnosed with vitamin D deficiency, according to Andrea Sikon, M.D., of the Cleveland Clinic Women's Health Center, and her associates.

The study involved a review of 1,114 consecutive dual energy x-ray absorptiometry (DXA) scans performed at the center from July 2002 to August 2003. Of these scans, 712 (64%) were considered indicative of osteopenia (a T score ranging from -1.1 to -2.4), or of osteoporosis (a T score of -2.5 or below), according to World Health Organization criteria.

An evaluation for secondary causes of low bone density was recommended by the interpreter reading the scans in 77 of the 712 women with z scores equal to or less than -1.5.

These 77 women were aged 27-84 years, with a mean of 53 years.

But only 49 (64%) of the 77 women actually had a secondary evaluation as recommended, and laboratory tests were drawn only in 42 (55%) of these women.

Most of the specialists—which included rheumatologists, osteoporosis specialists, and North American Menopause Society-certified women's health specialists—followed up with patients as recommended, compared with less than one-third of primary care physicians, which included general ob.gyns., internists, and family physicians who practiced at the Cleveland Clinic.

Of the 41 women whose DXA scan had been ordered by a specialist, 39 (95%) had a secondary work-up initiated by the physician. But among the 36 whose primary care physician had ordered the DXA scan, only 10 (28%) had a work-up, according to the investigators.

Of the 42 women who had the full work-up, including lab tests, 23 (55%) were diagnosed with vitamin D deficiency, 4 (9%) were diagnosed with primary hyperparathyroidism, and 5 (12%) were diagnosed with premature ovarian insufficiency.

Concluding that specialists were more likely to perform the secondary evaluation, the study authors recommended that vitamin D, 25-hydroxyvitamin D, and parathyroid hormone levels should be drawn on all women with z scores that are at or below -1.5.

In an interview with this newspaper, study investigator Holly L. Thacker, M.D., who is the head of the Cleveland Clinic Women's Health Center, said it is unclear whether the physicians read the entire report or perhaps did not know which secondary work-up to conduct.

WASHINGTON — Primary care physicians are less likely than specialists to initiate a work-up for secondary causes of bone loss in patients with scans indicating low bone density, despite a recommendation to do so.

That finding emerged from a study presented in poster form during the annual meeting of the North American Menopause Society.

Some patients with scans indicating osteoporosis were premenopausal women who started treatment with a bisphosphonate after their physicians received the scan results. Eventually, however, these patients were diagnosed with vitamin D deficiency, according to Andrea Sikon, M.D., of the Cleveland Clinic Women's Health Center, and her associates.

The study involved a review of 1,114 consecutive dual energy x-ray absorptiometry (DXA) scans performed at the center from July 2002 to August 2003. Of these scans, 712 (64%) were considered indicative of osteopenia (a T score ranging from -1.1 to -2.4), or of osteoporosis (a T score of -2.5 or below), according to World Health Organization criteria.

An evaluation for secondary causes of low bone density was recommended by the interpreter reading the scans in 77 of the 712 women with z scores equal to or less than -1.5.

These 77 women were aged 27-84 years, with a mean of 53 years.

But only 49 (64%) of the 77 women actually had a secondary evaluation as recommended, and laboratory tests were drawn only in 42 (55%) of these women.

Most of the specialists—which included rheumatologists, osteoporosis specialists, and North American Menopause Society-certified women's health specialists—followed up with patients as recommended, compared with less than one-third of primary care physicians, which included general ob.gyns., internists, and family physicians who practiced at the Cleveland Clinic.

Of the 41 women whose DXA scan had been ordered by a specialist, 39 (95%) had a secondary work-up initiated by the physician. But among the 36 whose primary care physician had ordered the DXA scan, only 10 (28%) had a work-up, according to the investigators.

Of the 42 women who had the full work-up, including lab tests, 23 (55%) were diagnosed with vitamin D deficiency, 4 (9%) were diagnosed with primary hyperparathyroidism, and 5 (12%) were diagnosed with premature ovarian insufficiency.

Concluding that specialists were more likely to perform the secondary evaluation, the study authors recommended that vitamin D, 25-hydroxyvitamin D, and parathyroid hormone levels should be drawn on all women with z scores that are at or below -1.5.

In an interview with this newspaper, study investigator Holly L. Thacker, M.D., who is the head of the Cleveland Clinic Women's Health Center, said it is unclear whether the physicians read the entire report or perhaps did not know which secondary work-up to conduct.

WASHINGTON — Primary care physicians are less likely than specialists to initiate a work-up for secondary causes of bone loss in patients with scans indicating low bone density, despite a recommendation to do so.

That finding emerged from a study presented in poster form during the annual meeting of the North American Menopause Society.

Some patients with scans indicating osteoporosis were premenopausal women who started treatment with a bisphosphonate after their physicians received the scan results. Eventually, however, these patients were diagnosed with vitamin D deficiency, according to Andrea Sikon, M.D., of the Cleveland Clinic Women's Health Center, and her associates.

The study involved a review of 1,114 consecutive dual energy x-ray absorptiometry (DXA) scans performed at the center from July 2002 to August 2003. Of these scans, 712 (64%) were considered indicative of osteopenia (a T score ranging from -1.1 to -2.4), or of osteoporosis (a T score of -2.5 or below), according to World Health Organization criteria.

An evaluation for secondary causes of low bone density was recommended by the interpreter reading the scans in 77 of the 712 women with z scores equal to or less than -1.5.

These 77 women were aged 27-84 years, with a mean of 53 years.

But only 49 (64%) of the 77 women actually had a secondary evaluation as recommended, and laboratory tests were drawn only in 42 (55%) of these women.

Most of the specialists—which included rheumatologists, osteoporosis specialists, and North American Menopause Society-certified women's health specialists—followed up with patients as recommended, compared with less than one-third of primary care physicians, which included general ob.gyns., internists, and family physicians who practiced at the Cleveland Clinic.

Of the 41 women whose DXA scan had been ordered by a specialist, 39 (95%) had a secondary work-up initiated by the physician. But among the 36 whose primary care physician had ordered the DXA scan, only 10 (28%) had a work-up, according to the investigators.

Of the 42 women who had the full work-up, including lab tests, 23 (55%) were diagnosed with vitamin D deficiency, 4 (9%) were diagnosed with primary hyperparathyroidism, and 5 (12%) were diagnosed with premature ovarian insufficiency.

Concluding that specialists were more likely to perform the secondary evaluation, the study authors recommended that vitamin D, 25-hydroxyvitamin D, and parathyroid hormone levels should be drawn on all women with z scores that are at or below -1.5.

In an interview with this newspaper, study investigator Holly L. Thacker, M.D., who is the head of the Cleveland Clinic Women's Health Center, said it is unclear whether the physicians read the entire report or perhaps did not know which secondary work-up to conduct.

An intrathecal formulation of a synthetic version of a toxin used by a fish-eating marine snail to catch its prey has been approved as a treatment for severe, chronic pain.

The Food and Drug Administration approved ziconotide for intrathecal (IT) infusion for managing severe chronic pain “in patients for whom intrathecal therapy is warranted and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or IT morphine.” It is being marketed under the trade name Prialt by Elan Pharmaceuticals Inc.

Ziconotide, which is not an opioid, is a synthetic version of a conopeptide used by a species of marine snail, Conus magus, to sting fish. In nature the toxin “is so powerful it stops the fish dead in its track, and the snail eats it,” said Mark Wallace, M.D., director of the center for pain and palliative medicine at the University of California, San Diego.

The synthetic version is an N-type calcium channel antagonist. N-type calcium channels are located mainly in the dorsal horn cells of the spinal cord, predominantly on the superficial layers, in the area of substantia gelatinosa where pain fibers synapse, Dr. Wallace explained. Ziconotide “blocks those calcium channels at the level where these pain fibers meet up,” essentially shutting them down, he said.

The three trials that led to approval included patients with “really refractory” pain due to causes such as low back pain, cancer pain, neuropathic pain, pain from nervous system injuries, and HIV-related pain, said Dr. Wallace, an investigator in the studies and a consultant to the manufacturer.

The three pivotal trials used the Visual Analog Scale of Pain Intensity (VASPI), as the primary end point.

The most recent trial was a multicenter study in 220 patients with severe chronic pain, described by most as refractory to treatments including IT morphine. Patients were first taken off IT medications and stabilized on analgesics that included opiates and the treated with placebo or ziconotide. At 3 weeks, VASPI scores had improved by a mean of 12% from baseline vs. a 5% mean improvement for patients on placebo, a highly significant difference. During treatment, the use of non-IT opioids dropped by 24% among patients on ziconotide, compared with 17% among those on placebo.

Dr. Wallace said ziconotide is not associated with addiction, withdrawal, or tolerance, and it is not a controlled substance. The most common side effects are neurologic, including neurocognitive impairment and dizziness.

The drug comes with a black box warning about possible severe psychiatric symptoms and neurologic impairment during treatment, and it is contraindicated in people with a history of psychosis.

An intrathecal formulation of a synthetic version of a toxin used by a fish-eating marine snail to catch its prey has been approved as a treatment for severe, chronic pain.

The Food and Drug Administration approved ziconotide for intrathecal (IT) infusion for managing severe chronic pain “in patients for whom intrathecal therapy is warranted and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or IT morphine.” It is being marketed under the trade name Prialt by Elan Pharmaceuticals Inc.

Ziconotide, which is not an opioid, is a synthetic version of a conopeptide used by a species of marine snail, Conus magus, to sting fish. In nature the toxin “is so powerful it stops the fish dead in its track, and the snail eats it,” said Mark Wallace, M.D., director of the center for pain and palliative medicine at the University of California, San Diego.

The synthetic version is an N-type calcium channel antagonist. N-type calcium channels are located mainly in the dorsal horn cells of the spinal cord, predominantly on the superficial layers, in the area of substantia gelatinosa where pain fibers synapse, Dr. Wallace explained. Ziconotide “blocks those calcium channels at the level where these pain fibers meet up,” essentially shutting them down, he said.

The three trials that led to approval included patients with “really refractory” pain due to causes such as low back pain, cancer pain, neuropathic pain, pain from nervous system injuries, and HIV-related pain, said Dr. Wallace, an investigator in the studies and a consultant to the manufacturer.

The three pivotal trials used the Visual Analog Scale of Pain Intensity (VASPI), as the primary end point.

The most recent trial was a multicenter study in 220 patients with severe chronic pain, described by most as refractory to treatments including IT morphine. Patients were first taken off IT medications and stabilized on analgesics that included opiates and the treated with placebo or ziconotide. At 3 weeks, VASPI scores had improved by a mean of 12% from baseline vs. a 5% mean improvement for patients on placebo, a highly significant difference. During treatment, the use of non-IT opioids dropped by 24% among patients on ziconotide, compared with 17% among those on placebo.

Dr. Wallace said ziconotide is not associated with addiction, withdrawal, or tolerance, and it is not a controlled substance. The most common side effects are neurologic, including neurocognitive impairment and dizziness.

The drug comes with a black box warning about possible severe psychiatric symptoms and neurologic impairment during treatment, and it is contraindicated in people with a history of psychosis.

An intrathecal formulation of a synthetic version of a toxin used by a fish-eating marine snail to catch its prey has been approved as a treatment for severe, chronic pain.

The Food and Drug Administration approved ziconotide for intrathecal (IT) infusion for managing severe chronic pain “in patients for whom intrathecal therapy is warranted and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or IT morphine.” It is being marketed under the trade name Prialt by Elan Pharmaceuticals Inc.

Ziconotide, which is not an opioid, is a synthetic version of a conopeptide used by a species of marine snail, Conus magus, to sting fish. In nature the toxin “is so powerful it stops the fish dead in its track, and the snail eats it,” said Mark Wallace, M.D., director of the center for pain and palliative medicine at the University of California, San Diego.

The synthetic version is an N-type calcium channel antagonist. N-type calcium channels are located mainly in the dorsal horn cells of the spinal cord, predominantly on the superficial layers, in the area of substantia gelatinosa where pain fibers synapse, Dr. Wallace explained. Ziconotide “blocks those calcium channels at the level where these pain fibers meet up,” essentially shutting them down, he said.

The three trials that led to approval included patients with “really refractory” pain due to causes such as low back pain, cancer pain, neuropathic pain, pain from nervous system injuries, and HIV-related pain, said Dr. Wallace, an investigator in the studies and a consultant to the manufacturer.

The three pivotal trials used the Visual Analog Scale of Pain Intensity (VASPI), as the primary end point.

The most recent trial was a multicenter study in 220 patients with severe chronic pain, described by most as refractory to treatments including IT morphine. Patients were first taken off IT medications and stabilized on analgesics that included opiates and the treated with placebo or ziconotide. At 3 weeks, VASPI scores had improved by a mean of 12% from baseline vs. a 5% mean improvement for patients on placebo, a highly significant difference. During treatment, the use of non-IT opioids dropped by 24% among patients on ziconotide, compared with 17% among those on placebo.

Dr. Wallace said ziconotide is not associated with addiction, withdrawal, or tolerance, and it is not a controlled substance. The most common side effects are neurologic, including neurocognitive impairment and dizziness.

The drug comes with a black box warning about possible severe psychiatric symptoms and neurologic impairment during treatment, and it is contraindicated in people with a history of psychosis.

WASHINGTON — Primary care physicians are less likely than specialists to initiate a work-up for secondary causes of bone loss in patients with scans indicating low bone density, despite a recommendation to do so.

That finding emerged from a study presented in poster form at the annual meeting of the North American Menopause Society.

Some patients with scans indicating osteoporosis were premenopausal women who started treatment with a bisphosphonate after their physicians received the scan results. Eventually, however, these patients were diagnosed with vitamin D deficiency, according to Andrea Sikon, M.D., of the Cleveland Clinic Women's Health Center, and her associates.

The study involved a review of 1,114 consecutive dual energy x-ray absorptiometry (DXA) scans performed at the center from July 2002 to August 2003. Of these scans, 712 (64%) were considered indicative of osteopenia (a T score ranging from −1.1 to −2.4), or of osteoporosis (a T score of −2.5 or below), according to World Health Organization criteria.

An evaluation for secondary causes of low bone density was recommended by the interpreter reading the scans in 77 of the 712 women with z scores equal to or less than −1.5. These 77 women were aged 27 to 84 years, with a mean of 53 years.

But only 49 (64%) of the 77 women actually had a secondary evaluation as recommended, and laboratory tests were drawn only in 42 (55%) of these women.

Most of the specialists—which included rheumatologists, osteoporosis specialists, and North American Menopause Society-certified women's health specialists—followed up with patients as recommended, compared with less than one-third of primary care physicians, which included general ob.gyns., internists, and family physicians at the Cleveland Clinic.

Of the 41 women whose DXA scan had been ordered by a specialist, 39 (95%) had a secondary work-up initiated by the physician. But among the 36 whose primary care physician had ordered the DXA scan, only 10 (28%) had a work-up.

Of the 42 women who had the full work-up, including lab tests, 23 (55%) were diagnosed with vitamin D deficiency, 4 (9%) were diagnosed with primary hyperparathyroidism, and 5 (12%) were diagnosed with premature ovarian insufficiency.

Concluding that specialists were more likely to perform the secondary evaluation, the authors recommended that vitamin D, 25-hydroxyvitamin D, and parathyroid hormone levels should be drawn on all women with z scores at or below −1.5.

In an interview with this newspaper, study investigator Holly L. Thacker, M.D., head of the Cleveland Clinic Women's Health Center, said it is unclear whether the physicians read the entire report or perhaps did not know which secondary work-up to conduct.

WASHINGTON — Primary care physicians are less likely than specialists to initiate a work-up for secondary causes of bone loss in patients with scans indicating low bone density, despite a recommendation to do so.

That finding emerged from a study presented in poster form at the annual meeting of the North American Menopause Society.

Some patients with scans indicating osteoporosis were premenopausal women who started treatment with a bisphosphonate after their physicians received the scan results. Eventually, however, these patients were diagnosed with vitamin D deficiency, according to Andrea Sikon, M.D., of the Cleveland Clinic Women's Health Center, and her associates.

The study involved a review of 1,114 consecutive dual energy x-ray absorptiometry (DXA) scans performed at the center from July 2002 to August 2003. Of these scans, 712 (64%) were considered indicative of osteopenia (a T score ranging from −1.1 to −2.4), or of osteoporosis (a T score of −2.5 or below), according to World Health Organization criteria.

An evaluation for secondary causes of low bone density was recommended by the interpreter reading the scans in 77 of the 712 women with z scores equal to or less than −1.5. These 77 women were aged 27 to 84 years, with a mean of 53 years.

But only 49 (64%) of the 77 women actually had a secondary evaluation as recommended, and laboratory tests were drawn only in 42 (55%) of these women.

Most of the specialists—which included rheumatologists, osteoporosis specialists, and North American Menopause Society-certified women's health specialists—followed up with patients as recommended, compared with less than one-third of primary care physicians, which included general ob.gyns., internists, and family physicians at the Cleveland Clinic.

Of the 41 women whose DXA scan had been ordered by a specialist, 39 (95%) had a secondary work-up initiated by the physician. But among the 36 whose primary care physician had ordered the DXA scan, only 10 (28%) had a work-up.

Of the 42 women who had the full work-up, including lab tests, 23 (55%) were diagnosed with vitamin D deficiency, 4 (9%) were diagnosed with primary hyperparathyroidism, and 5 (12%) were diagnosed with premature ovarian insufficiency.

Concluding that specialists were more likely to perform the secondary evaluation, the authors recommended that vitamin D, 25-hydroxyvitamin D, and parathyroid hormone levels should be drawn on all women with z scores at or below −1.5.

In an interview with this newspaper, study investigator Holly L. Thacker, M.D., head of the Cleveland Clinic Women's Health Center, said it is unclear whether the physicians read the entire report or perhaps did not know which secondary work-up to conduct.

WASHINGTON — Primary care physicians are less likely than specialists to initiate a work-up for secondary causes of bone loss in patients with scans indicating low bone density, despite a recommendation to do so.

That finding emerged from a study presented in poster form at the annual meeting of the North American Menopause Society.

Some patients with scans indicating osteoporosis were premenopausal women who started treatment with a bisphosphonate after their physicians received the scan results. Eventually, however, these patients were diagnosed with vitamin D deficiency, according to Andrea Sikon, M.D., of the Cleveland Clinic Women's Health Center, and her associates.

The study involved a review of 1,114 consecutive dual energy x-ray absorptiometry (DXA) scans performed at the center from July 2002 to August 2003. Of these scans, 712 (64%) were considered indicative of osteopenia (a T score ranging from −1.1 to −2.4), or of osteoporosis (a T score of −2.5 or below), according to World Health Organization criteria.

An evaluation for secondary causes of low bone density was recommended by the interpreter reading the scans in 77 of the 712 women with z scores equal to or less than −1.5. These 77 women were aged 27 to 84 years, with a mean of 53 years.

But only 49 (64%) of the 77 women actually had a secondary evaluation as recommended, and laboratory tests were drawn only in 42 (55%) of these women.

Most of the specialists—which included rheumatologists, osteoporosis specialists, and North American Menopause Society-certified women's health specialists—followed up with patients as recommended, compared with less than one-third of primary care physicians, which included general ob.gyns., internists, and family physicians at the Cleveland Clinic.

Of the 41 women whose DXA scan had been ordered by a specialist, 39 (95%) had a secondary work-up initiated by the physician. But among the 36 whose primary care physician had ordered the DXA scan, only 10 (28%) had a work-up.

Of the 42 women who had the full work-up, including lab tests, 23 (55%) were diagnosed with vitamin D deficiency, 4 (9%) were diagnosed with primary hyperparathyroidism, and 5 (12%) were diagnosed with premature ovarian insufficiency.

Concluding that specialists were more likely to perform the secondary evaluation, the authors recommended that vitamin D, 25-hydroxyvitamin D, and parathyroid hormone levels should be drawn on all women with z scores at or below −1.5.

In an interview with this newspaper, study investigator Holly L. Thacker, M.D., head of the Cleveland Clinic Women's Health Center, said it is unclear whether the physicians read the entire report or perhaps did not know which secondary work-up to conduct.

BETHESDA, MD. — Concerns about the ability of consumers to correctly select themselves for treatment without the advice of a health care professional, less-than optimal therapy in people who need higher doses, and unintended pregnancy exposures were among those cited by Food and Drug Administration advisory panel members who voted against making low-dose lovastatin available over the counter.

At a joint meeting of the FDA's Nonprescription Drugs and Endocrinologic and Metabolic Drugs advisory committees last month, the panel voted 20–3 against recommending approval of the 20-mg dose of lovastatin (Mevacor) for OTC use. Merck proposed that the daily 20-mg dose—at a price of about $1 per pill—be approved for OTC marketing for men aged 45 and older and women 55 and older who have a moderate risk for coronary heart disease (CHD), an LDL-cholesterol level of 130–170 mg/dL, and two risk factors.

Merck developed an OTC label to guide consumers in determining whether they are candidates for treatment, and conducted a large, actual use study and a label comprehension study. This is the second time the company has requested an OTC switch for lovastatin: in 2000, the 10-mg dose was reviewed and rejected by the advisory panels and FDA for OTC use because of safety and efficacy concerns.

Panel members unanimously agreed that the target population proposed by Merck for the 20-mg dose merited cholesterol-lowering treatment with a statin, and that 20 mg/day was an effective dosage that would help a proportion of the population reach an LDL-cholesterol level below 130 mg/dL.

They also agreed that the 20-mg lovastatin dose was safe to use in the nonprescription setting without monitoring liver function, and, except for one member, agreed that the risk of muscle toxicity associated with the 20-mg lovastatin dose was “acceptable for an OTC drug.”

Several panel members who voted no said that they would have supported making the drug available OTC if there had been the option of “behind-the-counter” dispensing, which would give the pharmacists a role in counseling patients. This option is available in the United Kingdom, where the 20-mg dose of another Merck statin, atorvastatin (Zocor), was approved for OTC use last July. U.K. pharmacists are required to go over a questionnaire with prospective users and help them determine whether they are candidates for the lipid-lowering drug.

Michael McClung, M.D., director of the Oregon Osteoporosis Center, Portland, said he voted against approval not because he was concerned about effectiveness, but because of “my uncertainty about prospective patients to adequately assess their needs for choosing to take the therapy … and about whether this strategy is actually better than a physician-based approach.”

Neal Benowitz, M.D., chief of the division of clinical pharmacology, University of California, San Francisco, said he was in favor of nonprescription lovastatin, “but not for the system as proposed.” He said there needs to be a more adequate discussion of its benefits, better protection in terms of pregnancy risk, better care at the pharmacy level, and intervention on the part of the FDA to ensure that it would be marketed in a balanced way, if approved.

The three voting in favor of the approval included the panel chair, Alastair Wood, M.D., who said he believed that the 20-mg dose of lovastatin was safe and effective without the intervention of a physician.

“The vast majority of these [at risk] patients are receiving no therapy right now and should be,” agreed Dr. Wood, professor of medicine and pharmacology, Vanderbilt University, Nashville.

One panelist noted that with mass marketing, women younger than the target range would ultimately buy this medicine, and put themselves at risk.

The actual use study presented to the panel was an uncontrolled, multicenter study of 3,316 people in 14 shopping malls across the country, aimed primarily at observing the initial decisions consumers made in deciding whether to purchase lovastatin, and to continue using it.

Presenting the FDA analysis of the study, Daiva Shetty, M.D., of the division of OTC drug products, said that no new serious safety signals emerged, but the results indicated that OTC lovastatin would likely be used by women of childbearing age, consumers with contraindicated conditions, consumers with no or low CHD risk, and consumers at high risk for CHD.

Nearly 70% of users needed more information to decide whether to buy or use the product, nearly 48% were able to identify their LDL-cholesterol level, and 33% of users did not know their LDL-cholesterol levels at the initial visit. In addition, nearly 43% of users had fewer than two CHD risk factors, and 55% of users had one or more relative contraindications that were listed on the label. Of the users, 63% had a follow-up cholesterol test, as advised on the label, and 36% of those had achieved the LDL goal on the follow-up test.

Considering the actual use study, most of the panel said that while they agreed that the 20-mg dose was safe and effective, the results did not support the conclusion that the dose could safely and effectively be used in an OTC setting because of self-selection issues and the behavior of users after starting treatment. A large proportion of people in that study relied on a physician's advice for correctly self-selecting or self-diagnosing their need for a 20-mg dose, and most of the panel said that once OTC lovastatin was available, they would not expect consumers would have this much interaction with health care professionals about using it.

Furthermore, panelists generally agreed that the warning on the proposed label stating that the drug should not be used if pregnant or breast-feeding was inadequate. In the actual use study, nearly 41% of the users were women, but nearly 38% of these women were under age 55 and 22% were between the ages of 40 and 50 years, which includes women of childbearing potential, the FDA reviewer pointed out.

Like all statins, lovastatin is labeled pregnancy category X because there are no well-controlled studies in pregnant women, and there have been some postmarketing reports of fetal adverse effects on live births in pregnancies with first trimester exposure, as well as fetal and neonatal effects in animal studies, including skeletal anomalies at maternally toxic oral doses. This evidence would usually not result in a pregnancy contraindication for a drug, but because there is no benefit to temporarily treating hyperlipidemia during pregnancy, it is rated X.

Although lovastatin is available in generic form, if approved for OTC use, Merck would have exclusive rights to market it for 3 years. In December, Bristol-Myers Squibb announced plans to pursue approval of the 20-mg pravastatin (Pravachol) dose as an OTC treatment.

The vast majority of at-risk patients are receiving no therapy right now and should be, said panel chair Dr. Alastair Wood. James Reinaker

BETHESDA, MD. — Concerns about the ability of consumers to correctly select themselves for treatment without the advice of a health care professional, less-than optimal therapy in people who need higher doses, and unintended pregnancy exposures were among those cited by Food and Drug Administration advisory panel members who voted against making low-dose lovastatin available over the counter.

At a joint meeting of the FDA's Nonprescription Drugs and Endocrinologic and Metabolic Drugs advisory committees last month, the panel voted 20–3 against recommending approval of the 20-mg dose of lovastatin (Mevacor) for OTC use. Merck proposed that the daily 20-mg dose—at a price of about $1 per pill—be approved for OTC marketing for men aged 45 and older and women 55 and older who have a moderate risk for coronary heart disease (CHD), an LDL-cholesterol level of 130–170 mg/dL, and two risk factors.

Merck developed an OTC label to guide consumers in determining whether they are candidates for treatment, and conducted a large, actual use study and a label comprehension study. This is the second time the company has requested an OTC switch for lovastatin: in 2000, the 10-mg dose was reviewed and rejected by the advisory panels and FDA for OTC use because of safety and efficacy concerns.

Panel members unanimously agreed that the target population proposed by Merck for the 20-mg dose merited cholesterol-lowering treatment with a statin, and that 20 mg/day was an effective dosage that would help a proportion of the population reach an LDL-cholesterol level below 130 mg/dL.

They also agreed that the 20-mg lovastatin dose was safe to use in the nonprescription setting without monitoring liver function, and, except for one member, agreed that the risk of muscle toxicity associated with the 20-mg lovastatin dose was “acceptable for an OTC drug.”

Several panel members who voted no said that they would have supported making the drug available OTC if there had been the option of “behind-the-counter” dispensing, which would give the pharmacists a role in counseling patients. This option is available in the United Kingdom, where the 20-mg dose of another Merck statin, atorvastatin (Zocor), was approved for OTC use last July. U.K. pharmacists are required to go over a questionnaire with prospective users and help them determine whether they are candidates for the lipid-lowering drug.

Michael McClung, M.D., director of the Oregon Osteoporosis Center, Portland, said he voted against approval not because he was concerned about effectiveness, but because of “my uncertainty about prospective patients to adequately assess their needs for choosing to take the therapy … and about whether this strategy is actually better than a physician-based approach.”

Neal Benowitz, M.D., chief of the division of clinical pharmacology, University of California, San Francisco, said he was in favor of nonprescription lovastatin, “but not for the system as proposed.” He said there needs to be a more adequate discussion of its benefits, better protection in terms of pregnancy risk, better care at the pharmacy level, and intervention on the part of the FDA to ensure that it would be marketed in a balanced way, if approved.

The three voting in favor of the approval included the panel chair, Alastair Wood, M.D., who said he believed that the 20-mg dose of lovastatin was safe and effective without the intervention of a physician.

“The vast majority of these [at risk] patients are receiving no therapy right now and should be,” agreed Dr. Wood, professor of medicine and pharmacology, Vanderbilt University, Nashville.

One panelist noted that with mass marketing, women younger than the target range would ultimately buy this medicine, and put themselves at risk.

The actual use study presented to the panel was an uncontrolled, multicenter study of 3,316 people in 14 shopping malls across the country, aimed primarily at observing the initial decisions consumers made in deciding whether to purchase lovastatin, and to continue using it.

Presenting the FDA analysis of the study, Daiva Shetty, M.D., of the division of OTC drug products, said that no new serious safety signals emerged, but the results indicated that OTC lovastatin would likely be used by women of childbearing age, consumers with contraindicated conditions, consumers with no or low CHD risk, and consumers at high risk for CHD.

Nearly 70% of users needed more information to decide whether to buy or use the product, nearly 48% were able to identify their LDL-cholesterol level, and 33% of users did not know their LDL-cholesterol levels at the initial visit. In addition, nearly 43% of users had fewer than two CHD risk factors, and 55% of users had one or more relative contraindications that were listed on the label. Of the users, 63% had a follow-up cholesterol test, as advised on the label, and 36% of those had achieved the LDL goal on the follow-up test.

Considering the actual use study, most of the panel said that while they agreed that the 20-mg dose was safe and effective, the results did not support the conclusion that the dose could safely and effectively be used in an OTC setting because of self-selection issues and the behavior of users after starting treatment. A large proportion of people in that study relied on a physician's advice for correctly self-selecting or self-diagnosing their need for a 20-mg dose, and most of the panel said that once OTC lovastatin was available, they would not expect consumers would have this much interaction with health care professionals about using it.

Furthermore, panelists generally agreed that the warning on the proposed label stating that the drug should not be used if pregnant or breast-feeding was inadequate. In the actual use study, nearly 41% of the users were women, but nearly 38% of these women were under age 55 and 22% were between the ages of 40 and 50 years, which includes women of childbearing potential, the FDA reviewer pointed out.

Like all statins, lovastatin is labeled pregnancy category X because there are no well-controlled studies in pregnant women, and there have been some postmarketing reports of fetal adverse effects on live births in pregnancies with first trimester exposure, as well as fetal and neonatal effects in animal studies, including skeletal anomalies at maternally toxic oral doses. This evidence would usually not result in a pregnancy contraindication for a drug, but because there is no benefit to temporarily treating hyperlipidemia during pregnancy, it is rated X.

Although lovastatin is available in generic form, if approved for OTC use, Merck would have exclusive rights to market it for 3 years. In December, Bristol-Myers Squibb announced plans to pursue approval of the 20-mg pravastatin (Pravachol) dose as an OTC treatment.

The vast majority of at-risk patients are receiving no therapy right now and should be, said panel chair Dr. Alastair Wood. James Reinaker

BETHESDA, MD. — Concerns about the ability of consumers to correctly select themselves for treatment without the advice of a health care professional, less-than optimal therapy in people who need higher doses, and unintended pregnancy exposures were among those cited by Food and Drug Administration advisory panel members who voted against making low-dose lovastatin available over the counter.

At a joint meeting of the FDA's Nonprescription Drugs and Endocrinologic and Metabolic Drugs advisory committees last month, the panel voted 20–3 against recommending approval of the 20-mg dose of lovastatin (Mevacor) for OTC use. Merck proposed that the daily 20-mg dose—at a price of about $1 per pill—be approved for OTC marketing for men aged 45 and older and women 55 and older who have a moderate risk for coronary heart disease (CHD), an LDL-cholesterol level of 130–170 mg/dL, and two risk factors.

Merck developed an OTC label to guide consumers in determining whether they are candidates for treatment, and conducted a large, actual use study and a label comprehension study. This is the second time the company has requested an OTC switch for lovastatin: in 2000, the 10-mg dose was reviewed and rejected by the advisory panels and FDA for OTC use because of safety and efficacy concerns.

Panel members unanimously agreed that the target population proposed by Merck for the 20-mg dose merited cholesterol-lowering treatment with a statin, and that 20 mg/day was an effective dosage that would help a proportion of the population reach an LDL-cholesterol level below 130 mg/dL.

They also agreed that the 20-mg lovastatin dose was safe to use in the nonprescription setting without monitoring liver function, and, except for one member, agreed that the risk of muscle toxicity associated with the 20-mg lovastatin dose was “acceptable for an OTC drug.”

Several panel members who voted no said that they would have supported making the drug available OTC if there had been the option of “behind-the-counter” dispensing, which would give the pharmacists a role in counseling patients. This option is available in the United Kingdom, where the 20-mg dose of another Merck statin, atorvastatin (Zocor), was approved for OTC use last July. U.K. pharmacists are required to go over a questionnaire with prospective users and help them determine whether they are candidates for the lipid-lowering drug.

Michael McClung, M.D., director of the Oregon Osteoporosis Center, Portland, said he voted against approval not because he was concerned about effectiveness, but because of “my uncertainty about prospective patients to adequately assess their needs for choosing to take the therapy … and about whether this strategy is actually better than a physician-based approach.”

Neal Benowitz, M.D., chief of the division of clinical pharmacology, University of California, San Francisco, said he was in favor of nonprescription lovastatin, “but not for the system as proposed.” He said there needs to be a more adequate discussion of its benefits, better protection in terms of pregnancy risk, better care at the pharmacy level, and intervention on the part of the FDA to ensure that it would be marketed in a balanced way, if approved.

The three voting in favor of the approval included the panel chair, Alastair Wood, M.D., who said he believed that the 20-mg dose of lovastatin was safe and effective without the intervention of a physician.

“The vast majority of these [at risk] patients are receiving no therapy right now and should be,” agreed Dr. Wood, professor of medicine and pharmacology, Vanderbilt University, Nashville.

One panelist noted that with mass marketing, women younger than the target range would ultimately buy this medicine, and put themselves at risk.

The actual use study presented to the panel was an uncontrolled, multicenter study of 3,316 people in 14 shopping malls across the country, aimed primarily at observing the initial decisions consumers made in deciding whether to purchase lovastatin, and to continue using it.

Presenting the FDA analysis of the study, Daiva Shetty, M.D., of the division of OTC drug products, said that no new serious safety signals emerged, but the results indicated that OTC lovastatin would likely be used by women of childbearing age, consumers with contraindicated conditions, consumers with no or low CHD risk, and consumers at high risk for CHD.

Nearly 70% of users needed more information to decide whether to buy or use the product, nearly 48% were able to identify their LDL-cholesterol level, and 33% of users did not know their LDL-cholesterol levels at the initial visit. In addition, nearly 43% of users had fewer than two CHD risk factors, and 55% of users had one or more relative contraindications that were listed on the label. Of the users, 63% had a follow-up cholesterol test, as advised on the label, and 36% of those had achieved the LDL goal on the follow-up test.

Considering the actual use study, most of the panel said that while they agreed that the 20-mg dose was safe and effective, the results did not support the conclusion that the dose could safely and effectively be used in an OTC setting because of self-selection issues and the behavior of users after starting treatment. A large proportion of people in that study relied on a physician's advice for correctly self-selecting or self-diagnosing their need for a 20-mg dose, and most of the panel said that once OTC lovastatin was available, they would not expect consumers would have this much interaction with health care professionals about using it.

Furthermore, panelists generally agreed that the warning on the proposed label stating that the drug should not be used if pregnant or breast-feeding was inadequate. In the actual use study, nearly 41% of the users were women, but nearly 38% of these women were under age 55 and 22% were between the ages of 40 and 50 years, which includes women of childbearing potential, the FDA reviewer pointed out.

Like all statins, lovastatin is labeled pregnancy category X because there are no well-controlled studies in pregnant women, and there have been some postmarketing reports of fetal adverse effects on live births in pregnancies with first trimester exposure, as well as fetal and neonatal effects in animal studies, including skeletal anomalies at maternally toxic oral doses. This evidence would usually not result in a pregnancy contraindication for a drug, but because there is no benefit to temporarily treating hyperlipidemia during pregnancy, it is rated X.

Although lovastatin is available in generic form, if approved for OTC use, Merck would have exclusive rights to market it for 3 years. In December, Bristol-Myers Squibb announced plans to pursue approval of the 20-mg pravastatin (Pravachol) dose as an OTC treatment.

The vast majority of at-risk patients are receiving no therapy right now and should be, said panel chair Dr. Alastair Wood. James Reinaker