Elizabeth Mechcatie

The combination of phentermine and topiramate has been approved for the treatment of weight loss with stipulations: a risk evaluation and mitigation strategy that addresses the potential teratogenic and adverse cardiac effects of the product, according to the Food and Drug Administration.

In the widely anticipated FDA announcement on July 17, Dr. Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, said in a statement that the phentermine-topiramate combination "used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides another treatment option for chronic weight management in Americans who are obese or are overweight and have at least one weight-related comorbid condition."

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities.

The product contains an immediate-release formulation of phentermine, a sympathomimetic amine approved for short-term weight loss that has been marketed in the United States since 1959; and a controlled-release formulation of topiramate, approved for treating adult epilepsy in 1996, migraine prophylaxis in 2004, and pediatric epilepsy in 2011.

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities, in combination with diet and exercise.

The risk evaluation and mitigation strategy (REMS) addresses the teratogenicity of topiramate, which is known to increase the risk of oral clefts at the higher doses used for treating epilepsy, and the possible adverse cardiac effects of phentermine, which increases the pulse rate. The REMS includes a patient medication guide that is provided with each filled prescription, health care provider training, and distribution of the product through certified pharmacies.

It will be marketed as Qsymia by Vivus, not Qnexa, the original proposed trade name. After a starting dose of 3.75 mg/23 mg of phentermine/topiramate daily for 2 weeks, the recommended dose is 7.5 mg of phentermine with 46 mg of extended-release topiramate. A higher dose (15 mg/92 mg) is available for select patients who do not reach their weight-loss goal. These phentermine and topiramate doses are lower than the doses available for the two products available separately.

"Females of reproductive potential must not be pregnant when starting Qsymia therapy or become pregnant while taking Qsymia," should have a negative pregnancy test before starting treatment and monthly during treatment, and should consistently use effective contraception while on the weight-loss drug, according to the FDA statement. If a patient on treatment does not lose at least 5% of body weight after 12 weeks on the higher dose, treatment should be stopped, "as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment," the statement added.

Approval was based on the results of two, 1-year studies involving nearly 4,000 obese and overweight people, mostly white females, with and without significant comorbidities, comparing phentermine-topiramate to placebo. Patients on the recommended and the higher doses of phentermine-topiramate lost an average of 6.7% and 8.9% of their weight, respectively, over those on placebo. About 62% of those on the recommended dose and 69% of those on the highest dose lost at least 5% of their baseline body weight, compared with about 20% of those on placebo. The most common side effects associated with treatment are paresthesias, dizziness, altered taste sensation, insomnia, constipation, and dry mouth.

In the studies, those who had not lost at least 3% of their body weight by week 12 of treatment were unlikely to achieve and sustain weight loss with continued treatment. As a result, it’s recommended that patients be evaluated by 12 weeks to determine whether they should stop treatment or start the higher dose, according to the FDA.

At a meeting in February, the majority of an FDA advisory panel voted that the benefit-risk profile of the medication supported its approval, with panelists in favor of approval citing evidence in clinical trials that treatment was associated with substantial weight loss and a favorable impact on obesity-related comorbidities in some patients, and the small number of effective nonsurgical weight loss treatments currently available. However, they stressed that the drug should be used only in appropriate patients, and they remained concerned about increases in pulse rate associated with treatment; the potential for cardiac adverse events; and the potential for an increased risk of oral clefts, although that risk may be lower than with the higher doses used for epilepsy and migraine prophylaxis, they said.

When the advisory panel first reviewed the phentermine-topiramate combination in July 2010, the majority voted against approval because of concerns about associated teratogenicity and increases in heart rate (by a mean of 1.6 beats/min at the highest dose). At the FDA’s request, the company studied the cardiovascular risks and teratogenic potential further and developed the REMS.

Vivus is required to conduct 10 postmarketing studies, including long-term cardiovascular outcomes studies in overweight and obese people with cardiovascular disease, studies in obese children and adolescents, and studies to evaluate drug utilization and pregnancy exposures. The company expects to make the drug available in the fourth quarter of 2012.

This is the second drug product approved for weight loss in 13 years. In June, the FDA approved lorcaserin hydrochloride (Belviq), a selective serotonin 2C receptor agonist at a dosage of 10 mg twice a day for the same indication.

Click here for prescribing information.

The combination of phentermine and topiramate has been approved for the treatment of weight loss with stipulations: a risk evaluation and mitigation strategy that addresses the potential teratogenic and adverse cardiac effects of the product, according to the Food and Drug Administration.

In the widely anticipated FDA announcement on July 17, Dr. Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, said in a statement that the phentermine-topiramate combination "used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides another treatment option for chronic weight management in Americans who are obese or are overweight and have at least one weight-related comorbid condition."

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities.

The product contains an immediate-release formulation of phentermine, a sympathomimetic amine approved for short-term weight loss that has been marketed in the United States since 1959; and a controlled-release formulation of topiramate, approved for treating adult epilepsy in 1996, migraine prophylaxis in 2004, and pediatric epilepsy in 2011.

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities, in combination with diet and exercise.

The risk evaluation and mitigation strategy (REMS) addresses the teratogenicity of topiramate, which is known to increase the risk of oral clefts at the higher doses used for treating epilepsy, and the possible adverse cardiac effects of phentermine, which increases the pulse rate. The REMS includes a patient medication guide that is provided with each filled prescription, health care provider training, and distribution of the product through certified pharmacies.

It will be marketed as Qsymia by Vivus, not Qnexa, the original proposed trade name. After a starting dose of 3.75 mg/23 mg of phentermine/topiramate daily for 2 weeks, the recommended dose is 7.5 mg of phentermine with 46 mg of extended-release topiramate. A higher dose (15 mg/92 mg) is available for select patients who do not reach their weight-loss goal. These phentermine and topiramate doses are lower than the doses available for the two products available separately.

"Females of reproductive potential must not be pregnant when starting Qsymia therapy or become pregnant while taking Qsymia," should have a negative pregnancy test before starting treatment and monthly during treatment, and should consistently use effective contraception while on the weight-loss drug, according to the FDA statement. If a patient on treatment does not lose at least 5% of body weight after 12 weeks on the higher dose, treatment should be stopped, "as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment," the statement added.

Approval was based on the results of two, 1-year studies involving nearly 4,000 obese and overweight people, mostly white females, with and without significant comorbidities, comparing phentermine-topiramate to placebo. Patients on the recommended and the higher doses of phentermine-topiramate lost an average of 6.7% and 8.9% of their weight, respectively, over those on placebo. About 62% of those on the recommended dose and 69% of those on the highest dose lost at least 5% of their baseline body weight, compared with about 20% of those on placebo. The most common side effects associated with treatment are paresthesias, dizziness, altered taste sensation, insomnia, constipation, and dry mouth.

In the studies, those who had not lost at least 3% of their body weight by week 12 of treatment were unlikely to achieve and sustain weight loss with continued treatment. As a result, it’s recommended that patients be evaluated by 12 weeks to determine whether they should stop treatment or start the higher dose, according to the FDA.

At a meeting in February, the majority of an FDA advisory panel voted that the benefit-risk profile of the medication supported its approval, with panelists in favor of approval citing evidence in clinical trials that treatment was associated with substantial weight loss and a favorable impact on obesity-related comorbidities in some patients, and the small number of effective nonsurgical weight loss treatments currently available. However, they stressed that the drug should be used only in appropriate patients, and they remained concerned about increases in pulse rate associated with treatment; the potential for cardiac adverse events; and the potential for an increased risk of oral clefts, although that risk may be lower than with the higher doses used for epilepsy and migraine prophylaxis, they said.

When the advisory panel first reviewed the phentermine-topiramate combination in July 2010, the majority voted against approval because of concerns about associated teratogenicity and increases in heart rate (by a mean of 1.6 beats/min at the highest dose). At the FDA’s request, the company studied the cardiovascular risks and teratogenic potential further and developed the REMS.

Vivus is required to conduct 10 postmarketing studies, including long-term cardiovascular outcomes studies in overweight and obese people with cardiovascular disease, studies in obese children and adolescents, and studies to evaluate drug utilization and pregnancy exposures. The company expects to make the drug available in the fourth quarter of 2012.

This is the second drug product approved for weight loss in 13 years. In June, the FDA approved lorcaserin hydrochloride (Belviq), a selective serotonin 2C receptor agonist at a dosage of 10 mg twice a day for the same indication.

Click here for prescribing information.

The combination of phentermine and topiramate has been approved for the treatment of weight loss with stipulations: a risk evaluation and mitigation strategy that addresses the potential teratogenic and adverse cardiac effects of the product, according to the Food and Drug Administration.

In the widely anticipated FDA announcement on July 17, Dr. Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, said in a statement that the phentermine-topiramate combination "used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides another treatment option for chronic weight management in Americans who are obese or are overweight and have at least one weight-related comorbid condition."

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities.

The product contains an immediate-release formulation of phentermine, a sympathomimetic amine approved for short-term weight loss that has been marketed in the United States since 1959; and a controlled-release formulation of topiramate, approved for treating adult epilepsy in 1996, migraine prophylaxis in 2004, and pediatric epilepsy in 2011.

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities, in combination with diet and exercise.

The risk evaluation and mitigation strategy (REMS) addresses the teratogenicity of topiramate, which is known to increase the risk of oral clefts at the higher doses used for treating epilepsy, and the possible adverse cardiac effects of phentermine, which increases the pulse rate. The REMS includes a patient medication guide that is provided with each filled prescription, health care provider training, and distribution of the product through certified pharmacies.

It will be marketed as Qsymia by Vivus, not Qnexa, the original proposed trade name. After a starting dose of 3.75 mg/23 mg of phentermine/topiramate daily for 2 weeks, the recommended dose is 7.5 mg of phentermine with 46 mg of extended-release topiramate. A higher dose (15 mg/92 mg) is available for select patients who do not reach their weight-loss goal. These phentermine and topiramate doses are lower than the doses available for the two products available separately.

"Females of reproductive potential must not be pregnant when starting Qsymia therapy or become pregnant while taking Qsymia," should have a negative pregnancy test before starting treatment and monthly during treatment, and should consistently use effective contraception while on the weight-loss drug, according to the FDA statement. If a patient on treatment does not lose at least 5% of body weight after 12 weeks on the higher dose, treatment should be stopped, "as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment," the statement added.

Approval was based on the results of two, 1-year studies involving nearly 4,000 obese and overweight people, mostly white females, with and without significant comorbidities, comparing phentermine-topiramate to placebo. Patients on the recommended and the higher doses of phentermine-topiramate lost an average of 6.7% and 8.9% of their weight, respectively, over those on placebo. About 62% of those on the recommended dose and 69% of those on the highest dose lost at least 5% of their baseline body weight, compared with about 20% of those on placebo. The most common side effects associated with treatment are paresthesias, dizziness, altered taste sensation, insomnia, constipation, and dry mouth.

In the studies, those who had not lost at least 3% of their body weight by week 12 of treatment were unlikely to achieve and sustain weight loss with continued treatment. As a result, it’s recommended that patients be evaluated by 12 weeks to determine whether they should stop treatment or start the higher dose, according to the FDA.

At a meeting in February, the majority of an FDA advisory panel voted that the benefit-risk profile of the medication supported its approval, with panelists in favor of approval citing evidence in clinical trials that treatment was associated with substantial weight loss and a favorable impact on obesity-related comorbidities in some patients, and the small number of effective nonsurgical weight loss treatments currently available. However, they stressed that the drug should be used only in appropriate patients, and they remained concerned about increases in pulse rate associated with treatment; the potential for cardiac adverse events; and the potential for an increased risk of oral clefts, although that risk may be lower than with the higher doses used for epilepsy and migraine prophylaxis, they said.

When the advisory panel first reviewed the phentermine-topiramate combination in July 2010, the majority voted against approval because of concerns about associated teratogenicity and increases in heart rate (by a mean of 1.6 beats/min at the highest dose). At the FDA’s request, the company studied the cardiovascular risks and teratogenic potential further and developed the REMS.

Vivus is required to conduct 10 postmarketing studies, including long-term cardiovascular outcomes studies in overweight and obese people with cardiovascular disease, studies in obese children and adolescents, and studies to evaluate drug utilization and pregnancy exposures. The company expects to make the drug available in the fourth quarter of 2012.

This is the second drug product approved for weight loss in 13 years. In June, the FDA approved lorcaserin hydrochloride (Belviq), a selective serotonin 2C receptor agonist at a dosage of 10 mg twice a day for the same indication.

Click here for prescribing information.

Another option for colon cleansing before colonoscopy is available, with the approval of a powder-based product that is dissolved in water and administered in two doses.

The product will be marketed as Prepopik by Ferring Pharmaceuticals, and will be available in October 2012, the company statement said.

The product is a combination of sodium picosulfate (a stimulant laxative) and magnesium oxide with anhydrous citric acid, which form magnesium citrate, an osmotic laxative. The patient receives two packets of powder to be dissolved in cold water and consumed at two different times, according to the Food and Drug Administration statement announcing the approval on July 17.

There are two options for when the product can be consumed in relation to the procedure time, according to the prescribing information. The "split-dose" method is preferred, and this involves taking the first dose the night before the colonoscopy and the second in the morning before the colonoscopy. Another option is to take the two doses in the afternoon and evening of the day before the procedure, with 6 hours between doses, known as the "day-before" method, the statement said. Additional clear fluids should be consumed after both dosing regimens.

Approval was based on two randomized clinical studies of about 1,200 adults undergoing a colonoscopy, who were assigned to the split-dose Prepopik regimen, the day-before Prepopik regimen, or a control regimen of polyethylene glycol plus electrolytes (PEG+E) with two 5-mg bisacodyl tablets taken the day before the colonoscopy.

In both studies, the use of Prepopik was as effective as the control preparation in cleansing the colon, but in the study that evaluated the split-dose regimen, this regimen was superior to the control preparation, the statement said.

The most common adverse events associated with Prepopik were nausea, vomiting, and headache. With split-dose Prepopik, the rates of nausea, vomiting, and headache were 2.6%, 1%, and 1.6%, respectively, compared with 3.7%, 3.4%, and 1.7% for the control regimen. With day-before Prepopik, rates of nausea, vomiting, and headache were 3%, 1.4%, and 2.7%, compared with 4.3%, 2%, and 1.7% for the control regimen.

On the day of colonoscopy, the rates of abnormal electrolyte shifts were numerically higher among those who used Prepopik, but the shifts were "transient in nature," according to the prescribing information.

In the statement, Dr. Victoria Kusiak, deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research, said, "The choice of a bowel cleansing regimen for colonoscopy should be based on a patient’s health and personal preferences."

As a condition of approval, Ferring is required to conduct studies to determine if the product is safe and effective in children.

Another option for colon cleansing before colonoscopy is available, with the approval of a powder-based product that is dissolved in water and administered in two doses.

The product will be marketed as Prepopik by Ferring Pharmaceuticals, and will be available in October 2012, the company statement said.

The product is a combination of sodium picosulfate (a stimulant laxative) and magnesium oxide with anhydrous citric acid, which form magnesium citrate, an osmotic laxative. The patient receives two packets of powder to be dissolved in cold water and consumed at two different times, according to the Food and Drug Administration statement announcing the approval on July 17.

There are two options for when the product can be consumed in relation to the procedure time, according to the prescribing information. The "split-dose" method is preferred, and this involves taking the first dose the night before the colonoscopy and the second in the morning before the colonoscopy. Another option is to take the two doses in the afternoon and evening of the day before the procedure, with 6 hours between doses, known as the "day-before" method, the statement said. Additional clear fluids should be consumed after both dosing regimens.

Approval was based on two randomized clinical studies of about 1,200 adults undergoing a colonoscopy, who were assigned to the split-dose Prepopik regimen, the day-before Prepopik regimen, or a control regimen of polyethylene glycol plus electrolytes (PEG+E) with two 5-mg bisacodyl tablets taken the day before the colonoscopy.

In both studies, the use of Prepopik was as effective as the control preparation in cleansing the colon, but in the study that evaluated the split-dose regimen, this regimen was superior to the control preparation, the statement said.

The most common adverse events associated with Prepopik were nausea, vomiting, and headache. With split-dose Prepopik, the rates of nausea, vomiting, and headache were 2.6%, 1%, and 1.6%, respectively, compared with 3.7%, 3.4%, and 1.7% for the control regimen. With day-before Prepopik, rates of nausea, vomiting, and headache were 3%, 1.4%, and 2.7%, compared with 4.3%, 2%, and 1.7% for the control regimen.

On the day of colonoscopy, the rates of abnormal electrolyte shifts were numerically higher among those who used Prepopik, but the shifts were "transient in nature," according to the prescribing information.

In the statement, Dr. Victoria Kusiak, deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research, said, "The choice of a bowel cleansing regimen for colonoscopy should be based on a patient’s health and personal preferences."

As a condition of approval, Ferring is required to conduct studies to determine if the product is safe and effective in children.

Another option for colon cleansing before colonoscopy is available, with the approval of a powder-based product that is dissolved in water and administered in two doses.

The product will be marketed as Prepopik by Ferring Pharmaceuticals, and will be available in October 2012, the company statement said.

The product is a combination of sodium picosulfate (a stimulant laxative) and magnesium oxide with anhydrous citric acid, which form magnesium citrate, an osmotic laxative. The patient receives two packets of powder to be dissolved in cold water and consumed at two different times, according to the Food and Drug Administration statement announcing the approval on July 17.

There are two options for when the product can be consumed in relation to the procedure time, according to the prescribing information. The "split-dose" method is preferred, and this involves taking the first dose the night before the colonoscopy and the second in the morning before the colonoscopy. Another option is to take the two doses in the afternoon and evening of the day before the procedure, with 6 hours between doses, known as the "day-before" method, the statement said. Additional clear fluids should be consumed after both dosing regimens.

Approval was based on two randomized clinical studies of about 1,200 adults undergoing a colonoscopy, who were assigned to the split-dose Prepopik regimen, the day-before Prepopik regimen, or a control regimen of polyethylene glycol plus electrolytes (PEG+E) with two 5-mg bisacodyl tablets taken the day before the colonoscopy.

In both studies, the use of Prepopik was as effective as the control preparation in cleansing the colon, but in the study that evaluated the split-dose regimen, this regimen was superior to the control preparation, the statement said.

The most common adverse events associated with Prepopik were nausea, vomiting, and headache. With split-dose Prepopik, the rates of nausea, vomiting, and headache were 2.6%, 1%, and 1.6%, respectively, compared with 3.7%, 3.4%, and 1.7% for the control regimen. With day-before Prepopik, rates of nausea, vomiting, and headache were 3%, 1.4%, and 2.7%, compared with 4.3%, 2%, and 1.7% for the control regimen.

On the day of colonoscopy, the rates of abnormal electrolyte shifts were numerically higher among those who used Prepopik, but the shifts were "transient in nature," according to the prescribing information.

In the statement, Dr. Victoria Kusiak, deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research, said, "The choice of a bowel cleansing regimen for colonoscopy should be based on a patient’s health and personal preferences."

As a condition of approval, Ferring is required to conduct studies to determine if the product is safe and effective in children.

Certain lots of Alere Triage cardiac diagnostic tests have been recalled because their use could result in an increase in false-positive or false-negative results, the Food and Drug Administration announced on July 11.

The recall may affect laboratory supplies: The statement says that there may not be enough of these products unaffected by the recall to meet the demand in all laboratories.

The recalled products – used to aid in the diagnosis of heart failure, myocardial infarction, and other conditions – are the Triage CardioProfiler Panel PN 97100CP, Triage Cardiac Panel PN 97000HS, Triage Profiler SOB Panel PN 97300, Triage BNP PN 98000XR, and Triage D-dimer PN 98100, according to a letter issued by the manufacturer, Alere San Diego.

As many as 98,100 test kits may be defective, the FDA statement said.

"There have been reports of patients receiving inappropriate clinical management which may have been due to such erroneous results," and the product "may cause serious adverse health consequences, including death," according to the FDA statement. Quality control tests may not detect false-positive and false-negative results within lots, which are unpredictable, the statement said. For example, some lots affected by the recall provide a troponin I result that is greater than 0.05 ng/mL, which additional testing determines is lower than 0.05 ng/mL.

The manufacturer is advising that the affected product be discarded, and that unaffected lots or other methods of performing these analyses be used instead.

The lot numbers of the recalled products are available at www.alere.com/assets/articles/TriageProductRecallLotsMay22.pdf.

The recall was initiated in May.

The recall notice is available at www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm311405.htm. The manufacturer can be contacted at 877-308-8287. Adverse events associated with any of these products should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch/.

Certain lots of Alere Triage cardiac diagnostic tests have been recalled because their use could result in an increase in false-positive or false-negative results, the Food and Drug Administration announced on July 11.

The recall may affect laboratory supplies: The statement says that there may not be enough of these products unaffected by the recall to meet the demand in all laboratories.

The recalled products – used to aid in the diagnosis of heart failure, myocardial infarction, and other conditions – are the Triage CardioProfiler Panel PN 97100CP, Triage Cardiac Panel PN 97000HS, Triage Profiler SOB Panel PN 97300, Triage BNP PN 98000XR, and Triage D-dimer PN 98100, according to a letter issued by the manufacturer, Alere San Diego.

As many as 98,100 test kits may be defective, the FDA statement said.

"There have been reports of patients receiving inappropriate clinical management which may have been due to such erroneous results," and the product "may cause serious adverse health consequences, including death," according to the FDA statement. Quality control tests may not detect false-positive and false-negative results within lots, which are unpredictable, the statement said. For example, some lots affected by the recall provide a troponin I result that is greater than 0.05 ng/mL, which additional testing determines is lower than 0.05 ng/mL.

The manufacturer is advising that the affected product be discarded, and that unaffected lots or other methods of performing these analyses be used instead.

The lot numbers of the recalled products are available at www.alere.com/assets/articles/TriageProductRecallLotsMay22.pdf.

The recall was initiated in May.

The recall notice is available at www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm311405.htm. The manufacturer can be contacted at 877-308-8287. Adverse events associated with any of these products should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch/.

Certain lots of Alere Triage cardiac diagnostic tests have been recalled because their use could result in an increase in false-positive or false-negative results, the Food and Drug Administration announced on July 11.

The recall may affect laboratory supplies: The statement says that there may not be enough of these products unaffected by the recall to meet the demand in all laboratories.

The recalled products – used to aid in the diagnosis of heart failure, myocardial infarction, and other conditions – are the Triage CardioProfiler Panel PN 97100CP, Triage Cardiac Panel PN 97000HS, Triage Profiler SOB Panel PN 97300, Triage BNP PN 98000XR, and Triage D-dimer PN 98100, according to a letter issued by the manufacturer, Alere San Diego.

As many as 98,100 test kits may be defective, the FDA statement said.

"There have been reports of patients receiving inappropriate clinical management which may have been due to such erroneous results," and the product "may cause serious adverse health consequences, including death," according to the FDA statement. Quality control tests may not detect false-positive and false-negative results within lots, which are unpredictable, the statement said. For example, some lots affected by the recall provide a troponin I result that is greater than 0.05 ng/mL, which additional testing determines is lower than 0.05 ng/mL.

The manufacturer is advising that the affected product be discarded, and that unaffected lots or other methods of performing these analyses be used instead.

The lot numbers of the recalled products are available at www.alere.com/assets/articles/TriageProductRecallLotsMay22.pdf.

The recall was initiated in May.

The recall notice is available at www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm311405.htm. The manufacturer can be contacted at 877-308-8287. Adverse events associated with any of these products should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch/.

With the long-awaited updated clinical guidelines for cholesterol testing and management in adults expected to be released this summer, some experts are hoping that the recommendations will abandon the central focus of previous guidelines: treating to low-density-lipoprotein cholesterol targets.

The Adult Treatment Panel IV (ATP IV) guidelines will be the first since ATP III was released in 2001, which, like ATP II, identified LDL cholesterol lowering as the primary goal of treatment and identified different targets for LDL-lowering drug treatment. An update of the ATP III guidelines released in 2004 also supported the ATP III treatment goal of LDL cholesterol below 100 mg/dL in people at high risk, but also recommended an LDL cholesterol goal of 70 mg/dL or lower for patients at very high CHD risk, based on clinical trial evidence that had become available.

No Evidence Base for Goals

As the release of the guidelines has gotten closer, there have been calls by some cardiologists that LDL targets be abandoned – most notably in an open letter to the ATP IV committee, published in January, in which Dr. Rodney Hayward of the University of Michigan and Dr. Harlan Krumholz of Yale University encouraged the committee to "abandon the paradigm of treating patients to LDL targets, a change that will better align ATP IV with current clinical evidence" (Circ. Cardiovasc. Qual. Outcomes 2012:2-5).

"The dogma that treating to target is based on clinical trial evidence belies the fact that no clinical trial has yet tested this strategy," they wrote, referring to evidence in clinical trials indicating "that the use of statins, and not treatment to target, can reduce risk."

A tailored treatment strategy with high-dose statins based on risk prevents more coronary events while treating fewer people, and will save more lives than approaches aimed at LDL targets, Dr. Krumholz said in an interview.

"What we know about statins is that they reliably reduce risk in populations regardless of their baseline cholesterol levels," and that the benefit of an intervention depends on a patient’s underlying risk and the degree to which that intervention can reduce the risk, said Dr. Krumholz, director of the Yale-New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation. "They seem to be effective no matter what the baseline LDL level is. So you’re not necessarily treating high cholesterol levels. At any level of cholesterol, it appears that these drugs lower risk."

He emphasized that he was not debating whether cholesterol is an underlying mechanism of atherosclerotic coronary heart disease. Rather, he considers statins as more of "a risk reduction pill" than a cholesterol reduction pill "because it doesn’t depend on someone’s cholesterol for its relative reduction in risk, so the people who benefit the most are the highest-risk patients."

In addition, Dr. Krumholz said that there has never been a large clinical trial that has sought to titrate patients to targets and evaluate outcomes, "so when people are identifying targets that everyone should be treated to, they are extrapolating data from many trials and drawing lines, but those are based on speculation." He cited the ACCORD study, which evaluated outcomes of tight glycemic control and found that achieving hemoglobin A_1c below 7% with an aggressive approach increased mortality.

By focusing on targets, he said, "you are agnostic to the strategy to get you to those targets." For example, recommending treatment to reduce cholesterol to below 70 mg/dL or 100 mg/dL implies using whatever means possible to achieve that goal and to use that metric to measure success.

Lab Results Aren’t Outcomes

The danger in that strategy is that there are drugs that reduce LDL or raise HDL that "don’t necessarily achieve outcomes that you would expect for patients," Dr. Krumholz said. For example, fenofibrate is promoted as lowering triglyceride levels and raising HDL levels, but two large trials of fenofibrate’s impact on patient outcomes have been negative and there have been no positive trials, he pointed out.

It is not yet known whether treatment with ezetimibe, an inhibitor of intestinal cholesterol absorption that reduces LDL cholesterol, improves patient outcomes – which is being studied in an ongoing trial – and this uncertainty is reflected in the drug’s label. "So the focus on the target often obscures the fact that not all drugs that can get you to target have been shown to improve outcomes," he added said. (The ezetimibe label includes the statement that the effect of the drug on cardiovascular morbidity and mortality "has not been determined.")

Then there are the recent examples of the once highly promising cholesteryl ester transfer protein (CETP) inhibitors. Torcetrapib, a potent CETP inhibitor, was associated with extremely favorable changes in HDL cholesterol levels as well as reductions in triglycerides and LDL cholesterol in a study that was terminated early because treatment was associated with an increase in mortality and cardiac events; the drug was never approved. If the manufacturer had not conducted this study, the degree of harm identified in the study would have been extremely difficult to detect once it was approved and used in clinical practice, said Dr. Krumholz, the Harold H. Hines Jr. Professor of Medicine and professor of investigative medicine and of public health at Yale University.

This is another example of a drug "doing great things to the lab test" that did not translate into clinical benefit, he said. "What we’re learning is that manipulating risk factors is tricky business, and some drugs and strategies may change them but will not favorably change the risk."

He also referred to the development of another CETP inhibitor, dalcetrapib, which was halted after what the manufacturer, Roche, recently announced was a lack of clinically meaningful efficacy of the drug in a phase III trial of patients with stable coronary heart disease following an acute coronary syndrome.

The lack of evidence that the targeted approach improves patient outcomes, he cited, includes the AIM-HIGH study, which found no additional benefit of niacin when added to statin therapy in patients with atherosclerotic cardiovascular disease and LDL cholesterol levels less than 70 mg/dL, even though niacin was associated with significant improvements in HDL cholesterol and triglyceride levels (N. Engl. J. Med. 2011;365:2255-67).

Dr. Krumholz also cited the JUPITER study, which found that treatment with rosuvastatin was associated with a significant reduction in major cardiovascular events among people who had LDL cholesterol levels below 130 mg/dL and elevated C-reactive protein levels (N. Engl. J. Med. 2008;359:2195-2207).

"We want to know that the strategies we employ actually help people and not just their lab tests, and even though the science is elegant that underlies the lipid hypothesis and no one is disputing the relationships and studies that have been conducted, we are beginning to recognize these drugs have a lot of effects," he said. "We know in an open population that these factors will predict risk, but don’t know whether changing them and that different strategies of changing them all have same benefit associated with them."

Recent concerns about reports of hyperglycemia and cognitive effects associated with statins emphasize that, for patients with little to gain from treatment, there is "no reason" to be exposed to this risk, but for those who have a lot to benefit from treatment, the risk may be worth taking, he said. In February, the Food and Drug Administration announced that memory loss and confusion associated with statins reversed once the statin was stopped and that reports of hyperglycemia had been added to statin labels.

A patient’s choice should also be considered, and when discussing treatment with patients, Dr. Krumholz likes to give them a sense of how many people need to take a medication like a statin for one person to benefit. "Even for a number that seems small, like 25, which is good in medicine, a patient may choose not to take it," he said, adding that treatment "should be customized, both to the patient’s preferences and to their risk."

Individual Risk Matters

In an interview, Dr. Robert Vogel, clinical professor at the University of Colorado, Denver, said that he agrees that the "the basic concept of getting to an LDL goal is wrong," and while he would not abandon LDL cholesterol as a risk factor, "I would certainly throw it out as a target." He said that this view is shared by a majority of lipidologists but a minority of cardiologists overall.

Courtesy Oscar G. Johnson VA Medical Center

He also cited the JUPITER study as well as the Treating to New Targets (TNT) study, which, he pointed out, compared two different atorvastatin doses, not two different LDL goals. This is representative of what is actually known – the effects of larger versus smaller treatment doses, or treatment versus placebo. "We never have tested treatment to specific goals," so those effects are unknown, but that "is how the ATP guidelines have been written," he noted.

In the TNT study of about 10,000 people with clinical evidence of CHD and LDL cholesterol levels below 130 mg/dL, intensive lipid lowering with 80 mg of atorvastatin was associated with a reduction in the risk of major coronary events that was significantly greater than that associated with 10 mg of atorvastatin daily (N. Engl. J. Med. 2005;352:1425-35).

Dr. Vogel said that he hoped that in ATP IV the concept of treating to goal will be changed to treating high-risk patients with high-dose effective statins, if tolerated, and matching treatment not to the LDL cholesterol, level but to an individual’s risk "or to the situation that has been demonstrated to be effective in prospective trials." This approach would be a substantial difference from previous guidelines and would be "changing more towards something that looks like treating heart failure," for which treatment is not based on particular parameters but on treatments that have been demonstrated to be effective.

Calls Met With Silence

Along with his colleague Dr. Michael Miller of the University of Maryland, Dr. Vogel tried to bring the issue to the forefront 3 years ago by writing an editorial entitled "Cholesterol Goals: Moving from Numbers to Treatment" (Clin. Cardiol. 2009;32:106-8). And 3 years earlier, Dr. Hayward and his associates wrote a review article concluding that "there is clear and compelling evidence that most patients at high risk for cardiovascular disease should be taking at least a moderate dose of a statin if tolerated, even if their natural LDL cholesterol level is low. We could find no published high-quality clinical evidence supporting titration of lipid therapy based on proposed LDL cholesterol targets" (Ann. Intern. Med. 2006;145:520-30).

These publications, and Dr. Krumholz’s letter earlier this year, have been answered with silence in the scientific literature.

VA Takes Tailored Approach

The Veterans Health Administration (VHA) is not waiting for guidelines to make the move to tailored treatment; it has already adopted this approach. Over the past 18 months, the country’s largest integrated health care system providing care to more than 8 million patients a year, has been reviewing the evidence on the role of LDL targets in managing cardiovascular risk, "particularly in light of concerns that performance measures tied too closely to targets might create incentives for overzealous pharmacotherapy that does not improve overall health," said Dr. Joe Francis, head of performance measurement for the VHA.

The Department of Veterans Affairs (VA) "determined that the strongest evidence supports treatment with statins as the core objective, independent of LDL target, so we reconfigured our internal performance measures to align with this evidence," he said in an interview. At the VA, lipid management in patients with ischemic heart disease or diabetes mellitus is now considered appropriate if the patient is on at least a moderate dose of a statin drug or the LDL is under 100 mg/dL, he added.

This decision was in line with recommendations issued by the American Heart Association and American College of Cardiology in November 2011, Dr. John Rumsfeld, national director of cardiology for the VA system, pointed out. Both he and Dr. Francis said they hoped that ATP IV will also be consistent with this evidence-based approach. Dr. Rumsfeld emphasized that the VHA performance measures "are not meant to supplant clinical judgment for individual cases where more aggressive treatment may be warranted."

Whether the panel is also headed in this direction could not be determined, as neither the panel chair, Dr. Neil J. Stone of Northwestern University, Chicago, nor the NHLBI press office would comment on the content of the report before its release. ATP IV is being developed simultaneously with updated reports on hypertension guidelines (JNC 8) and obesity guidelines (Obesity 2), which also are expected to be available for public review and comment this year and will be part of an integrated cardiovascular risk reduction guideline, according to the statement.

Dr. Krumholz said that he could not speculate as to what the recommendations will be, "but if they stick to the evidence, then they will transition ... to a different approach." Because of the public comment period after they are released, there will be ample opportunity for discussing and vetting the guidelines before they are finalized. What he considers most important is that "they adhere to the evidence and recognize that a target-based approach could lead to treatments with medicines that are yet unproven with regard to their benefit for patients."

Dr. Vogel suggested that the long delay in the release of ATP IV is an indicator that the panel is incorporating emerging data and likely struggling with the very issues detailed in this article.

The new guidelines, which will be in a draft format available for public review and comment, are expected to be released this summer, according to the National Heart, Lung, and Blood Institute.

None of the experts who contributed to this article had relevant financial disclosures.

With the long-awaited updated clinical guidelines for cholesterol testing and management in adults expected to be released this summer, some experts are hoping that the recommendations will abandon the central focus of previous guidelines: treating to low-density-lipoprotein cholesterol targets.

The Adult Treatment Panel IV (ATP IV) guidelines will be the first since ATP III was released in 2001, which, like ATP II, identified LDL cholesterol lowering as the primary goal of treatment and identified different targets for LDL-lowering drug treatment. An update of the ATP III guidelines released in 2004 also supported the ATP III treatment goal of LDL cholesterol below 100 mg/dL in people at high risk, but also recommended an LDL cholesterol goal of 70 mg/dL or lower for patients at very high CHD risk, based on clinical trial evidence that had become available.

No Evidence Base for Goals

As the release of the guidelines has gotten closer, there have been calls by some cardiologists that LDL targets be abandoned – most notably in an open letter to the ATP IV committee, published in January, in which Dr. Rodney Hayward of the University of Michigan and Dr. Harlan Krumholz of Yale University encouraged the committee to "abandon the paradigm of treating patients to LDL targets, a change that will better align ATP IV with current clinical evidence" (Circ. Cardiovasc. Qual. Outcomes 2012:2-5).

"The dogma that treating to target is based on clinical trial evidence belies the fact that no clinical trial has yet tested this strategy," they wrote, referring to evidence in clinical trials indicating "that the use of statins, and not treatment to target, can reduce risk."

A tailored treatment strategy with high-dose statins based on risk prevents more coronary events while treating fewer people, and will save more lives than approaches aimed at LDL targets, Dr. Krumholz said in an interview.

"What we know about statins is that they reliably reduce risk in populations regardless of their baseline cholesterol levels," and that the benefit of an intervention depends on a patient’s underlying risk and the degree to which that intervention can reduce the risk, said Dr. Krumholz, director of the Yale-New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation. "They seem to be effective no matter what the baseline LDL level is. So you’re not necessarily treating high cholesterol levels. At any level of cholesterol, it appears that these drugs lower risk."

He emphasized that he was not debating whether cholesterol is an underlying mechanism of atherosclerotic coronary heart disease. Rather, he considers statins as more of "a risk reduction pill" than a cholesterol reduction pill "because it doesn’t depend on someone’s cholesterol for its relative reduction in risk, so the people who benefit the most are the highest-risk patients."

In addition, Dr. Krumholz said that there has never been a large clinical trial that has sought to titrate patients to targets and evaluate outcomes, "so when people are identifying targets that everyone should be treated to, they are extrapolating data from many trials and drawing lines, but those are based on speculation." He cited the ACCORD study, which evaluated outcomes of tight glycemic control and found that achieving hemoglobin A_1c below 7% with an aggressive approach increased mortality.

By focusing on targets, he said, "you are agnostic to the strategy to get you to those targets." For example, recommending treatment to reduce cholesterol to below 70 mg/dL or 100 mg/dL implies using whatever means possible to achieve that goal and to use that metric to measure success.

Lab Results Aren’t Outcomes

The danger in that strategy is that there are drugs that reduce LDL or raise HDL that "don’t necessarily achieve outcomes that you would expect for patients," Dr. Krumholz said. For example, fenofibrate is promoted as lowering triglyceride levels and raising HDL levels, but two large trials of fenofibrate’s impact on patient outcomes have been negative and there have been no positive trials, he pointed out.

It is not yet known whether treatment with ezetimibe, an inhibitor of intestinal cholesterol absorption that reduces LDL cholesterol, improves patient outcomes – which is being studied in an ongoing trial – and this uncertainty is reflected in the drug’s label. "So the focus on the target often obscures the fact that not all drugs that can get you to target have been shown to improve outcomes," he added said. (The ezetimibe label includes the statement that the effect of the drug on cardiovascular morbidity and mortality "has not been determined.")

Then there are the recent examples of the once highly promising cholesteryl ester transfer protein (CETP) inhibitors. Torcetrapib, a potent CETP inhibitor, was associated with extremely favorable changes in HDL cholesterol levels as well as reductions in triglycerides and LDL cholesterol in a study that was terminated early because treatment was associated with an increase in mortality and cardiac events; the drug was never approved. If the manufacturer had not conducted this study, the degree of harm identified in the study would have been extremely difficult to detect once it was approved and used in clinical practice, said Dr. Krumholz, the Harold H. Hines Jr. Professor of Medicine and professor of investigative medicine and of public health at Yale University.

This is another example of a drug "doing great things to the lab test" that did not translate into clinical benefit, he said. "What we’re learning is that manipulating risk factors is tricky business, and some drugs and strategies may change them but will not favorably change the risk."

He also referred to the development of another CETP inhibitor, dalcetrapib, which was halted after what the manufacturer, Roche, recently announced was a lack of clinically meaningful efficacy of the drug in a phase III trial of patients with stable coronary heart disease following an acute coronary syndrome.

The lack of evidence that the targeted approach improves patient outcomes, he cited, includes the AIM-HIGH study, which found no additional benefit of niacin when added to statin therapy in patients with atherosclerotic cardiovascular disease and LDL cholesterol levels less than 70 mg/dL, even though niacin was associated with significant improvements in HDL cholesterol and triglyceride levels (N. Engl. J. Med. 2011;365:2255-67).

Dr. Krumholz also cited the JUPITER study, which found that treatment with rosuvastatin was associated with a significant reduction in major cardiovascular events among people who had LDL cholesterol levels below 130 mg/dL and elevated C-reactive protein levels (N. Engl. J. Med. 2008;359:2195-2207).

"We want to know that the strategies we employ actually help people and not just their lab tests, and even though the science is elegant that underlies the lipid hypothesis and no one is disputing the relationships and studies that have been conducted, we are beginning to recognize these drugs have a lot of effects," he said. "We know in an open population that these factors will predict risk, but don’t know whether changing them and that different strategies of changing them all have same benefit associated with them."

Recent concerns about reports of hyperglycemia and cognitive effects associated with statins emphasize that, for patients with little to gain from treatment, there is "no reason" to be exposed to this risk, but for those who have a lot to benefit from treatment, the risk may be worth taking, he said. In February, the Food and Drug Administration announced that memory loss and confusion associated with statins reversed once the statin was stopped and that reports of hyperglycemia had been added to statin labels.

A patient’s choice should also be considered, and when discussing treatment with patients, Dr. Krumholz likes to give them a sense of how many people need to take a medication like a statin for one person to benefit. "Even for a number that seems small, like 25, which is good in medicine, a patient may choose not to take it," he said, adding that treatment "should be customized, both to the patient’s preferences and to their risk."

Individual Risk Matters

In an interview, Dr. Robert Vogel, clinical professor at the University of Colorado, Denver, said that he agrees that the "the basic concept of getting to an LDL goal is wrong," and while he would not abandon LDL cholesterol as a risk factor, "I would certainly throw it out as a target." He said that this view is shared by a majority of lipidologists but a minority of cardiologists overall.

Courtesy Oscar G. Johnson VA Medical Center

He also cited the JUPITER study as well as the Treating to New Targets (TNT) study, which, he pointed out, compared two different atorvastatin doses, not two different LDL goals. This is representative of what is actually known – the effects of larger versus smaller treatment doses, or treatment versus placebo. "We never have tested treatment to specific goals," so those effects are unknown, but that "is how the ATP guidelines have been written," he noted.

In the TNT study of about 10,000 people with clinical evidence of CHD and LDL cholesterol levels below 130 mg/dL, intensive lipid lowering with 80 mg of atorvastatin was associated with a reduction in the risk of major coronary events that was significantly greater than that associated with 10 mg of atorvastatin daily (N. Engl. J. Med. 2005;352:1425-35).

Dr. Vogel said that he hoped that in ATP IV the concept of treating to goal will be changed to treating high-risk patients with high-dose effective statins, if tolerated, and matching treatment not to the LDL cholesterol, level but to an individual’s risk "or to the situation that has been demonstrated to be effective in prospective trials." This approach would be a substantial difference from previous guidelines and would be "changing more towards something that looks like treating heart failure," for which treatment is not based on particular parameters but on treatments that have been demonstrated to be effective.

Calls Met With Silence

Along with his colleague Dr. Michael Miller of the University of Maryland, Dr. Vogel tried to bring the issue to the forefront 3 years ago by writing an editorial entitled "Cholesterol Goals: Moving from Numbers to Treatment" (Clin. Cardiol. 2009;32:106-8). And 3 years earlier, Dr. Hayward and his associates wrote a review article concluding that "there is clear and compelling evidence that most patients at high risk for cardiovascular disease should be taking at least a moderate dose of a statin if tolerated, even if their natural LDL cholesterol level is low. We could find no published high-quality clinical evidence supporting titration of lipid therapy based on proposed LDL cholesterol targets" (Ann. Intern. Med. 2006;145:520-30).

These publications, and Dr. Krumholz’s letter earlier this year, have been answered with silence in the scientific literature.

VA Takes Tailored Approach

The Veterans Health Administration (VHA) is not waiting for guidelines to make the move to tailored treatment; it has already adopted this approach. Over the past 18 months, the country’s largest integrated health care system providing care to more than 8 million patients a year, has been reviewing the evidence on the role of LDL targets in managing cardiovascular risk, "particularly in light of concerns that performance measures tied too closely to targets might create incentives for overzealous pharmacotherapy that does not improve overall health," said Dr. Joe Francis, head of performance measurement for the VHA.

The Department of Veterans Affairs (VA) "determined that the strongest evidence supports treatment with statins as the core objective, independent of LDL target, so we reconfigured our internal performance measures to align with this evidence," he said in an interview. At the VA, lipid management in patients with ischemic heart disease or diabetes mellitus is now considered appropriate if the patient is on at least a moderate dose of a statin drug or the LDL is under 100 mg/dL, he added.

This decision was in line with recommendations issued by the American Heart Association and American College of Cardiology in November 2011, Dr. John Rumsfeld, national director of cardiology for the VA system, pointed out. Both he and Dr. Francis said they hoped that ATP IV will also be consistent with this evidence-based approach. Dr. Rumsfeld emphasized that the VHA performance measures "are not meant to supplant clinical judgment for individual cases where more aggressive treatment may be warranted."

Whether the panel is also headed in this direction could not be determined, as neither the panel chair, Dr. Neil J. Stone of Northwestern University, Chicago, nor the NHLBI press office would comment on the content of the report before its release. ATP IV is being developed simultaneously with updated reports on hypertension guidelines (JNC 8) and obesity guidelines (Obesity 2), which also are expected to be available for public review and comment this year and will be part of an integrated cardiovascular risk reduction guideline, according to the statement.

Dr. Krumholz said that he could not speculate as to what the recommendations will be, "but if they stick to the evidence, then they will transition ... to a different approach." Because of the public comment period after they are released, there will be ample opportunity for discussing and vetting the guidelines before they are finalized. What he considers most important is that "they adhere to the evidence and recognize that a target-based approach could lead to treatments with medicines that are yet unproven with regard to their benefit for patients."

Dr. Vogel suggested that the long delay in the release of ATP IV is an indicator that the panel is incorporating emerging data and likely struggling with the very issues detailed in this article.

The new guidelines, which will be in a draft format available for public review and comment, are expected to be released this summer, according to the National Heart, Lung, and Blood Institute.

None of the experts who contributed to this article had relevant financial disclosures.

With the long-awaited updated clinical guidelines for cholesterol testing and management in adults expected to be released this summer, some experts are hoping that the recommendations will abandon the central focus of previous guidelines: treating to low-density-lipoprotein cholesterol targets.

The Adult Treatment Panel IV (ATP IV) guidelines will be the first since ATP III was released in 2001, which, like ATP II, identified LDL cholesterol lowering as the primary goal of treatment and identified different targets for LDL-lowering drug treatment. An update of the ATP III guidelines released in 2004 also supported the ATP III treatment goal of LDL cholesterol below 100 mg/dL in people at high risk, but also recommended an LDL cholesterol goal of 70 mg/dL or lower for patients at very high CHD risk, based on clinical trial evidence that had become available.

No Evidence Base for Goals

As the release of the guidelines has gotten closer, there have been calls by some cardiologists that LDL targets be abandoned – most notably in an open letter to the ATP IV committee, published in January, in which Dr. Rodney Hayward of the University of Michigan and Dr. Harlan Krumholz of Yale University encouraged the committee to "abandon the paradigm of treating patients to LDL targets, a change that will better align ATP IV with current clinical evidence" (Circ. Cardiovasc. Qual. Outcomes 2012:2-5).

"The dogma that treating to target is based on clinical trial evidence belies the fact that no clinical trial has yet tested this strategy," they wrote, referring to evidence in clinical trials indicating "that the use of statins, and not treatment to target, can reduce risk."

A tailored treatment strategy with high-dose statins based on risk prevents more coronary events while treating fewer people, and will save more lives than approaches aimed at LDL targets, Dr. Krumholz said in an interview.

"What we know about statins is that they reliably reduce risk in populations regardless of their baseline cholesterol levels," and that the benefit of an intervention depends on a patient’s underlying risk and the degree to which that intervention can reduce the risk, said Dr. Krumholz, director of the Yale-New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation. "They seem to be effective no matter what the baseline LDL level is. So you’re not necessarily treating high cholesterol levels. At any level of cholesterol, it appears that these drugs lower risk."

He emphasized that he was not debating whether cholesterol is an underlying mechanism of atherosclerotic coronary heart disease. Rather, he considers statins as more of "a risk reduction pill" than a cholesterol reduction pill "because it doesn’t depend on someone’s cholesterol for its relative reduction in risk, so the people who benefit the most are the highest-risk patients."

In addition, Dr. Krumholz said that there has never been a large clinical trial that has sought to titrate patients to targets and evaluate outcomes, "so when people are identifying targets that everyone should be treated to, they are extrapolating data from many trials and drawing lines, but those are based on speculation." He cited the ACCORD study, which evaluated outcomes of tight glycemic control and found that achieving hemoglobin A_1c below 7% with an aggressive approach increased mortality.

By focusing on targets, he said, "you are agnostic to the strategy to get you to those targets." For example, recommending treatment to reduce cholesterol to below 70 mg/dL or 100 mg/dL implies using whatever means possible to achieve that goal and to use that metric to measure success.

Lab Results Aren’t Outcomes

The danger in that strategy is that there are drugs that reduce LDL or raise HDL that "don’t necessarily achieve outcomes that you would expect for patients," Dr. Krumholz said. For example, fenofibrate is promoted as lowering triglyceride levels and raising HDL levels, but two large trials of fenofibrate’s impact on patient outcomes have been negative and there have been no positive trials, he pointed out.

It is not yet known whether treatment with ezetimibe, an inhibitor of intestinal cholesterol absorption that reduces LDL cholesterol, improves patient outcomes – which is being studied in an ongoing trial – and this uncertainty is reflected in the drug’s label. "So the focus on the target often obscures the fact that not all drugs that can get you to target have been shown to improve outcomes," he added said. (The ezetimibe label includes the statement that the effect of the drug on cardiovascular morbidity and mortality "has not been determined.")

Then there are the recent examples of the once highly promising cholesteryl ester transfer protein (CETP) inhibitors. Torcetrapib, a potent CETP inhibitor, was associated with extremely favorable changes in HDL cholesterol levels as well as reductions in triglycerides and LDL cholesterol in a study that was terminated early because treatment was associated with an increase in mortality and cardiac events; the drug was never approved. If the manufacturer had not conducted this study, the degree of harm identified in the study would have been extremely difficult to detect once it was approved and used in clinical practice, said Dr. Krumholz, the Harold H. Hines Jr. Professor of Medicine and professor of investigative medicine and of public health at Yale University.

This is another example of a drug "doing great things to the lab test" that did not translate into clinical benefit, he said. "What we’re learning is that manipulating risk factors is tricky business, and some drugs and strategies may change them but will not favorably change the risk."

He also referred to the development of another CETP inhibitor, dalcetrapib, which was halted after what the manufacturer, Roche, recently announced was a lack of clinically meaningful efficacy of the drug in a phase III trial of patients with stable coronary heart disease following an acute coronary syndrome.

The lack of evidence that the targeted approach improves patient outcomes, he cited, includes the AIM-HIGH study, which found no additional benefit of niacin when added to statin therapy in patients with atherosclerotic cardiovascular disease and LDL cholesterol levels less than 70 mg/dL, even though niacin was associated with significant improvements in HDL cholesterol and triglyceride levels (N. Engl. J. Med. 2011;365:2255-67).

Dr. Krumholz also cited the JUPITER study, which found that treatment with rosuvastatin was associated with a significant reduction in major cardiovascular events among people who had LDL cholesterol levels below 130 mg/dL and elevated C-reactive protein levels (N. Engl. J. Med. 2008;359:2195-2207).

"We want to know that the strategies we employ actually help people and not just their lab tests, and even though the science is elegant that underlies the lipid hypothesis and no one is disputing the relationships and studies that have been conducted, we are beginning to recognize these drugs have a lot of effects," he said. "We know in an open population that these factors will predict risk, but don’t know whether changing them and that different strategies of changing them all have same benefit associated with them."

Recent concerns about reports of hyperglycemia and cognitive effects associated with statins emphasize that, for patients with little to gain from treatment, there is "no reason" to be exposed to this risk, but for those who have a lot to benefit from treatment, the risk may be worth taking, he said. In February, the Food and Drug Administration announced that memory loss and confusion associated with statins reversed once the statin was stopped and that reports of hyperglycemia had been added to statin labels.

A patient’s choice should also be considered, and when discussing treatment with patients, Dr. Krumholz likes to give them a sense of how many people need to take a medication like a statin for one person to benefit. "Even for a number that seems small, like 25, which is good in medicine, a patient may choose not to take it," he said, adding that treatment "should be customized, both to the patient’s preferences and to their risk."

Individual Risk Matters

In an interview, Dr. Robert Vogel, clinical professor at the University of Colorado, Denver, said that he agrees that the "the basic concept of getting to an LDL goal is wrong," and while he would not abandon LDL cholesterol as a risk factor, "I would certainly throw it out as a target." He said that this view is shared by a majority of lipidologists but a minority of cardiologists overall.

Courtesy Oscar G. Johnson VA Medical Center

He also cited the JUPITER study as well as the Treating to New Targets (TNT) study, which, he pointed out, compared two different atorvastatin doses, not two different LDL goals. This is representative of what is actually known – the effects of larger versus smaller treatment doses, or treatment versus placebo. "We never have tested treatment to specific goals," so those effects are unknown, but that "is how the ATP guidelines have been written," he noted.

In the TNT study of about 10,000 people with clinical evidence of CHD and LDL cholesterol levels below 130 mg/dL, intensive lipid lowering with 80 mg of atorvastatin was associated with a reduction in the risk of major coronary events that was significantly greater than that associated with 10 mg of atorvastatin daily (N. Engl. J. Med. 2005;352:1425-35).

Dr. Vogel said that he hoped that in ATP IV the concept of treating to goal will be changed to treating high-risk patients with high-dose effective statins, if tolerated, and matching treatment not to the LDL cholesterol, level but to an individual’s risk "or to the situation that has been demonstrated to be effective in prospective trials." This approach would be a substantial difference from previous guidelines and would be "changing more towards something that looks like treating heart failure," for which treatment is not based on particular parameters but on treatments that have been demonstrated to be effective.

Calls Met With Silence

Along with his colleague Dr. Michael Miller of the University of Maryland, Dr. Vogel tried to bring the issue to the forefront 3 years ago by writing an editorial entitled "Cholesterol Goals: Moving from Numbers to Treatment" (Clin. Cardiol. 2009;32:106-8). And 3 years earlier, Dr. Hayward and his associates wrote a review article concluding that "there is clear and compelling evidence that most patients at high risk for cardiovascular disease should be taking at least a moderate dose of a statin if tolerated, even if their natural LDL cholesterol level is low. We could find no published high-quality clinical evidence supporting titration of lipid therapy based on proposed LDL cholesterol targets" (Ann. Intern. Med. 2006;145:520-30).

These publications, and Dr. Krumholz’s letter earlier this year, have been answered with silence in the scientific literature.

VA Takes Tailored Approach

The Veterans Health Administration (VHA) is not waiting for guidelines to make the move to tailored treatment; it has already adopted this approach. Over the past 18 months, the country’s largest integrated health care system providing care to more than 8 million patients a year, has been reviewing the evidence on the role of LDL targets in managing cardiovascular risk, "particularly in light of concerns that performance measures tied too closely to targets might create incentives for overzealous pharmacotherapy that does not improve overall health," said Dr. Joe Francis, head of performance measurement for the VHA.

The Department of Veterans Affairs (VA) "determined that the strongest evidence supports treatment with statins as the core objective, independent of LDL target, so we reconfigured our internal performance measures to align with this evidence," he said in an interview. At the VA, lipid management in patients with ischemic heart disease or diabetes mellitus is now considered appropriate if the patient is on at least a moderate dose of a statin drug or the LDL is under 100 mg/dL, he added.

This decision was in line with recommendations issued by the American Heart Association and American College of Cardiology in November 2011, Dr. John Rumsfeld, national director of cardiology for the VA system, pointed out. Both he and Dr. Francis said they hoped that ATP IV will also be consistent with this evidence-based approach. Dr. Rumsfeld emphasized that the VHA performance measures "are not meant to supplant clinical judgment for individual cases where more aggressive treatment may be warranted."

Whether the panel is also headed in this direction could not be determined, as neither the panel chair, Dr. Neil J. Stone of Northwestern University, Chicago, nor the NHLBI press office would comment on the content of the report before its release. ATP IV is being developed simultaneously with updated reports on hypertension guidelines (JNC 8) and obesity guidelines (Obesity 2), which also are expected to be available for public review and comment this year and will be part of an integrated cardiovascular risk reduction guideline, according to the statement.

Dr. Krumholz said that he could not speculate as to what the recommendations will be, "but if they stick to the evidence, then they will transition ... to a different approach." Because of the public comment period after they are released, there will be ample opportunity for discussing and vetting the guidelines before they are finalized. What he considers most important is that "they adhere to the evidence and recognize that a target-based approach could lead to treatments with medicines that are yet unproven with regard to their benefit for patients."

Dr. Vogel suggested that the long delay in the release of ATP IV is an indicator that the panel is incorporating emerging data and likely struggling with the very issues detailed in this article.

The new guidelines, which will be in a draft format available for public review and comment, are expected to be released this summer, according to the National Heart, Lung, and Blood Institute.

None of the experts who contributed to this article had relevant financial disclosures.

The Food and Drug Administration has approved a new cetuximab indication in colorectal cancer along with a genetic test to rule out patients who carry a KRAS mutation and therefore would not benefit from treatment.

The new indication supports use of cetuximab (Erbitux) combined with the three-drug FOLFIRI chemotherapy regimen as a first-line treatment for patients with metastatic colorectal cancer that expresses the epidermal growth factor receptor (EGFR) targeted by cetuximab. The indication is contingent on the patients not having a KRAS mutation, since cetuximab does not work in those patients.

Concurrently, the agency approved the therascreen KRAS RGQ PCR Kit, which provides information about KRAS mutations in patients with metastatic colorectal cancer, and "provides a reliable way to identify these subsets of patients with colon cancer," according to the FDA announcement.

The genetic assay, manufactured by Qiagen, is a real-time polymerase chain reaction assay that detects 7 different mutations of the KRAS gene in a tumor specimen, the agency said on July 6.

"The approval of this new Erbitux indication with the concurrent approval of a genetic test provides clear guidance on selecting patients who will optimally benefit," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, is quoted in the agency’s announcement.

"Clinical trial data leading to the approval of this new indication support the recommendation to treat those patients whose colorectal tumors do not have KRAS mutations and to avoid treating those with KRAS mutations," he added.

Approval of the indication for cetuximab with FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) is based on retrospective analyses of subsets of patients in three trials: the CRYSTAL study and two supportive studies (CA225025 and EMR 62 202-047 [OPUS]), which determined that the benefits of cetuximab "were limited to patients whose tumors did not have one of the seven KRAS mutations detected by the test," according to the FDA statement.

Treatment with cetuximab was associated with improvements in overall survival, progression-free survival, and overall response rates in the subset of patients with KRAS wild-type tumors, but among those with KRAS mutant tumors, "there was no benefit or potential harm." the FDA said.

In the open-label, randomized controlled CRYSTAL trial patients with EGFR-expressing metastatic colorectal cancer received FOLFIRI with or without cetuximab. A retrospective analysis found that 63% of patients had KRAS wild-type tumors, while the remaining 37% had KRAS mutations.

Overall survival reached a median of 23.5 months with cetuximab and FOLFIRI in the wild-type patients vs. 19.5 months with FOLFIRI alone. Median progression-free survival also was longer with the combination at 9.5 months vs. 8.1 months. No significant improvements were seen in patients with KRAS mutations.

The CA225025 and OPUS trials added cetuximab to best supportive care and to the FOLFOX regimen, respectively. In both studies the benefit from cetuximab was limited to patients with wild type KRAS.

Safety data in these studies was consistent with the adverse event profiles of cetuximab and the chemotherapy regimens, according to the announcement.

The FDA recommends that cetuximab be administered at 400 mg/m² intravenously as a 120-minute infusion initially followed by 250 mg/m² infused over 30 minutes weekly in combination with FOLFIRI. It said cetuximab administration should be completed 1 hour prior to FOLFIRI.

Cetuximab, marketed as Erbitux by ImClone, received accelerated approval in 2004 to treat late-stage colorectal cancer in patients who had stopped responding to irinotecan-based chemotherapy. In 2007, the FDA granted regular approval for single-agent cetuximab "for the treatment of patients with EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based chemotherapy regimens."

It also is approved in the treatment of head and neck cancers.

The genetic test kit was developed by Qiagen of Manchester, England. Erbitux is marketed by Bristol-Myers Squibb and Eli Lilly.

Click here to view the updated cetuximab label.

The Food and Drug Administration has approved a new cetuximab indication in colorectal cancer along with a genetic test to rule out patients who carry a KRAS mutation and therefore would not benefit from treatment.

The new indication supports use of cetuximab (Erbitux) combined with the three-drug FOLFIRI chemotherapy regimen as a first-line treatment for patients with metastatic colorectal cancer that expresses the epidermal growth factor receptor (EGFR) targeted by cetuximab. The indication is contingent on the patients not having a KRAS mutation, since cetuximab does not work in those patients.

Concurrently, the agency approved the therascreen KRAS RGQ PCR Kit, which provides information about KRAS mutations in patients with metastatic colorectal cancer, and "provides a reliable way to identify these subsets of patients with colon cancer," according to the FDA announcement.

The genetic assay, manufactured by Qiagen, is a real-time polymerase chain reaction assay that detects 7 different mutations of the KRAS gene in a tumor specimen, the agency said on July 6.

"The approval of this new Erbitux indication with the concurrent approval of a genetic test provides clear guidance on selecting patients who will optimally benefit," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, is quoted in the agency’s announcement.

"Clinical trial data leading to the approval of this new indication support the recommendation to treat those patients whose colorectal tumors do not have KRAS mutations and to avoid treating those with KRAS mutations," he added.

Approval of the indication for cetuximab with FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) is based on retrospective analyses of subsets of patients in three trials: the CRYSTAL study and two supportive studies (CA225025 and EMR 62 202-047 [OPUS]), which determined that the benefits of cetuximab "were limited to patients whose tumors did not have one of the seven KRAS mutations detected by the test," according to the FDA statement.

Treatment with cetuximab was associated with improvements in overall survival, progression-free survival, and overall response rates in the subset of patients with KRAS wild-type tumors, but among those with KRAS mutant tumors, "there was no benefit or potential harm." the FDA said.

In the open-label, randomized controlled CRYSTAL trial patients with EGFR-expressing metastatic colorectal cancer received FOLFIRI with or without cetuximab. A retrospective analysis found that 63% of patients had KRAS wild-type tumors, while the remaining 37% had KRAS mutations.

Overall survival reached a median of 23.5 months with cetuximab and FOLFIRI in the wild-type patients vs. 19.5 months with FOLFIRI alone. Median progression-free survival also was longer with the combination at 9.5 months vs. 8.1 months. No significant improvements were seen in patients with KRAS mutations.

The CA225025 and OPUS trials added cetuximab to best supportive care and to the FOLFOX regimen, respectively. In both studies the benefit from cetuximab was limited to patients with wild type KRAS.

Safety data in these studies was consistent with the adverse event profiles of cetuximab and the chemotherapy regimens, according to the announcement.

The FDA recommends that cetuximab be administered at 400 mg/m² intravenously as a 120-minute infusion initially followed by 250 mg/m² infused over 30 minutes weekly in combination with FOLFIRI. It said cetuximab administration should be completed 1 hour prior to FOLFIRI.

Cetuximab, marketed as Erbitux by ImClone, received accelerated approval in 2004 to treat late-stage colorectal cancer in patients who had stopped responding to irinotecan-based chemotherapy. In 2007, the FDA granted regular approval for single-agent cetuximab "for the treatment of patients with EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based chemotherapy regimens."

It also is approved in the treatment of head and neck cancers.

The genetic test kit was developed by Qiagen of Manchester, England. Erbitux is marketed by Bristol-Myers Squibb and Eli Lilly.

Click here to view the updated cetuximab label.

The Food and Drug Administration has approved a new cetuximab indication in colorectal cancer along with a genetic test to rule out patients who carry a KRAS mutation and therefore would not benefit from treatment.

The new indication supports use of cetuximab (Erbitux) combined with the three-drug FOLFIRI chemotherapy regimen as a first-line treatment for patients with metastatic colorectal cancer that expresses the epidermal growth factor receptor (EGFR) targeted by cetuximab. The indication is contingent on the patients not having a KRAS mutation, since cetuximab does not work in those patients.

Concurrently, the agency approved the therascreen KRAS RGQ PCR Kit, which provides information about KRAS mutations in patients with metastatic colorectal cancer, and "provides a reliable way to identify these subsets of patients with colon cancer," according to the FDA announcement.

The genetic assay, manufactured by Qiagen, is a real-time polymerase chain reaction assay that detects 7 different mutations of the KRAS gene in a tumor specimen, the agency said on July 6.

"The approval of this new Erbitux indication with the concurrent approval of a genetic test provides clear guidance on selecting patients who will optimally benefit," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, is quoted in the agency’s announcement.

"Clinical trial data leading to the approval of this new indication support the recommendation to treat those patients whose colorectal tumors do not have KRAS mutations and to avoid treating those with KRAS mutations," he added.

Approval of the indication for cetuximab with FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) is based on retrospective analyses of subsets of patients in three trials: the CRYSTAL study and two supportive studies (CA225025 and EMR 62 202-047 [OPUS]), which determined that the benefits of cetuximab "were limited to patients whose tumors did not have one of the seven KRAS mutations detected by the test," according to the FDA statement.

Treatment with cetuximab was associated with improvements in overall survival, progression-free survival, and overall response rates in the subset of patients with KRAS wild-type tumors, but among those with KRAS mutant tumors, "there was no benefit or potential harm." the FDA said.

In the open-label, randomized controlled CRYSTAL trial patients with EGFR-expressing metastatic colorectal cancer received FOLFIRI with or without cetuximab. A retrospective analysis found that 63% of patients had KRAS wild-type tumors, while the remaining 37% had KRAS mutations.

Overall survival reached a median of 23.5 months with cetuximab and FOLFIRI in the wild-type patients vs. 19.5 months with FOLFIRI alone. Median progression-free survival also was longer with the combination at 9.5 months vs. 8.1 months. No significant improvements were seen in patients with KRAS mutations.

The CA225025 and OPUS trials added cetuximab to best supportive care and to the FOLFOX regimen, respectively. In both studies the benefit from cetuximab was limited to patients with wild type KRAS.

Safety data in these studies was consistent with the adverse event profiles of cetuximab and the chemotherapy regimens, according to the announcement.

The FDA recommends that cetuximab be administered at 400 mg/m² intravenously as a 120-minute infusion initially followed by 250 mg/m² infused over 30 minutes weekly in combination with FOLFIRI. It said cetuximab administration should be completed 1 hour prior to FOLFIRI.

Cetuximab, marketed as Erbitux by ImClone, received accelerated approval in 2004 to treat late-stage colorectal cancer in patients who had stopped responding to irinotecan-based chemotherapy. In 2007, the FDA granted regular approval for single-agent cetuximab "for the treatment of patients with EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based chemotherapy regimens."

It also is approved in the treatment of head and neck cancers.

The genetic test kit was developed by Qiagen of Manchester, England. Erbitux is marketed by Bristol-Myers Squibb and Eli Lilly.

Click here to view the updated cetuximab label.

Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.

GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.

The updated label will say that ondansetron, a 5-HT₃ receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.

The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.

Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.

The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.

It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.

Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.

The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.

Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.

GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.

The updated label will say that ondansetron, a 5-HT₃ receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.

The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.

Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.

The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.

It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.

Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.

The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.

Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.

GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.

The updated label will say that ondansetron, a 5-HT₃ receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.

The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.

Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.

The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.

It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.

Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.

The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.

Three lots of leucovorin calcium injection manufactured by Bedford Laboratories have been recalled because of crystalline particulate matter that is visible in some vials, the Food and Drug Administration announced on July 6.

The nationwide recall applies to lots that were shipped between January and June 2011, and expire in 2013. The particulate matter identified is the active drug substance, according to the FDA and a statement by the company, a division of Ben Venue Laboratories in Bedford, Ohio.

Courtesy of FDA

To date, no foreign matter has been identified, both said, and no adverse reactions have been reported in association with any of the recalled lots.

Particulate matter is considered a potential health hazard in that it can case vein irritation and phlebitis, clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylactic shock, and death, according to the FDA and Bedford.

Leucovorin is widely used in oncology, with indications for rescue after high-dose methotrexate administration in osteosarcoma as well as to counteract methotrexate toxicity, impaired methotrexate elimination, and inadvertent overdoses of folic acid antagonists. It is also indicated in the treatment of megaloblastic anemias caused by folic acid deficiency, when oral therapy is not feasible; and in combination with 5-fluorouracil in patients with advanced colorectal cancer.

Leucovorin is one of the generic cancer drugs in short supply, according to an FDA listing of current drug shortages. Bedford Laboratories cited "manufacturing delays" for the limited availability of its leucovorin products in an entry last updated April 10, 2012.

Lot numbers of the recalled products are: 2017620, 2038374, and 2038374A. Health care practitioners are advised to quarantine recalled vials for return to the company.

Adverse reactions associated with the recalled leucovorin lots should be reported to the manufacturer at 800-521-5169 or the FDA at 800-332-1088 or www.fda.gov/medwatch.

Three lots of leucovorin calcium injection manufactured by Bedford Laboratories have been recalled because of crystalline particulate matter that is visible in some vials, the Food and Drug Administration announced on July 6.

The nationwide recall applies to lots that were shipped between January and June 2011, and expire in 2013. The particulate matter identified is the active drug substance, according to the FDA and a statement by the company, a division of Ben Venue Laboratories in Bedford, Ohio.

Courtesy of FDA

To date, no foreign matter has been identified, both said, and no adverse reactions have been reported in association with any of the recalled lots.

Particulate matter is considered a potential health hazard in that it can case vein irritation and phlebitis, clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylactic shock, and death, according to the FDA and Bedford.

Leucovorin is widely used in oncology, with indications for rescue after high-dose methotrexate administration in osteosarcoma as well as to counteract methotrexate toxicity, impaired methotrexate elimination, and inadvertent overdoses of folic acid antagonists. It is also indicated in the treatment of megaloblastic anemias caused by folic acid deficiency, when oral therapy is not feasible; and in combination with 5-fluorouracil in patients with advanced colorectal cancer.

Leucovorin is one of the generic cancer drugs in short supply, according to an FDA listing of current drug shortages. Bedford Laboratories cited "manufacturing delays" for the limited availability of its leucovorin products in an entry last updated April 10, 2012.

Lot numbers of the recalled products are: 2017620, 2038374, and 2038374A. Health care practitioners are advised to quarantine recalled vials for return to the company.

Adverse reactions associated with the recalled leucovorin lots should be reported to the manufacturer at 800-521-5169 or the FDA at 800-332-1088 or www.fda.gov/medwatch.

Three lots of leucovorin calcium injection manufactured by Bedford Laboratories have been recalled because of crystalline particulate matter that is visible in some vials, the Food and Drug Administration announced on July 6.

The nationwide recall applies to lots that were shipped between January and June 2011, and expire in 2013. The particulate matter identified is the active drug substance, according to the FDA and a statement by the company, a division of Ben Venue Laboratories in Bedford, Ohio.

Courtesy of FDA

To date, no foreign matter has been identified, both said, and no adverse reactions have been reported in association with any of the recalled lots.

Particulate matter is considered a potential health hazard in that it can case vein irritation and phlebitis, clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylactic shock, and death, according to the FDA and Bedford.

Leucovorin is widely used in oncology, with indications for rescue after high-dose methotrexate administration in osteosarcoma as well as to counteract methotrexate toxicity, impaired methotrexate elimination, and inadvertent overdoses of folic acid antagonists. It is also indicated in the treatment of megaloblastic anemias caused by folic acid deficiency, when oral therapy is not feasible; and in combination with 5-fluorouracil in patients with advanced colorectal cancer.

Leucovorin is one of the generic cancer drugs in short supply, according to an FDA listing of current drug shortages. Bedford Laboratories cited "manufacturing delays" for the limited availability of its leucovorin products in an entry last updated April 10, 2012.

Lot numbers of the recalled products are: 2017620, 2038374, and 2038374A. Health care practitioners are advised to quarantine recalled vials for return to the company.

Adverse reactions associated with the recalled leucovorin lots should be reported to the manufacturer at 800-521-5169 or the FDA at 800-332-1088 or www.fda.gov/medwatch.

Most medical devices distributed in the United States should carry an identification label to help identify and resolve problems associated with them, according to a statement issued the Food and Drug Administration on July 3.

The unique device identifier (UDI), an exclusive numeric or alphanumeric code, "has the potential to improve the quality of information in medical device adverse event reports, which will help the FDA identify product problems more quickly, better target recalls and improve patient safety," according to the statement.

FDA

In the proposed rule, the label will include an illustration of the device, the product name, its expiration date, reference and lot numbers, manufacturer information, as well as a bar code.

The UDI system is required by legislation passed by Congress in 2007 directing the agency to develop regulations establishing such a system, and the agency worked closely with industry, clinical groups, as well as patient and consumer groups, and has conducted four pilot studies in developing the proposed rule, according to the statement.

Implementation will be phased in, with the highest-risk medical devices labeled first. Low-risk devices will be exempt from some or all of the requirements and over-the-counter devices will be exempt, since they usually have a universal product code.

In addition to improving the accuracy of device-related adverse event reporting, the system is expected to expedite the resolution of device-related problems. The system also will address counterfeit products and medical emergency preparation.

The FDA is accepting comments on the proposal for 120 days. 

Most medical devices distributed in the United States should carry an identification label to help identify and resolve problems associated with them, according to a statement issued the Food and Drug Administration on July 3.

The unique device identifier (UDI), an exclusive numeric or alphanumeric code, "has the potential to improve the quality of information in medical device adverse event reports, which will help the FDA identify product problems more quickly, better target recalls and improve patient safety," according to the statement.

FDA

In the proposed rule, the label will include an illustration of the device, the product name, its expiration date, reference and lot numbers, manufacturer information, as well as a bar code.

The UDI system is required by legislation passed by Congress in 2007 directing the agency to develop regulations establishing such a system, and the agency worked closely with industry, clinical groups, as well as patient and consumer groups, and has conducted four pilot studies in developing the proposed rule, according to the statement.

Implementation will be phased in, with the highest-risk medical devices labeled first. Low-risk devices will be exempt from some or all of the requirements and over-the-counter devices will be exempt, since they usually have a universal product code.

In addition to improving the accuracy of device-related adverse event reporting, the system is expected to expedite the resolution of device-related problems. The system also will address counterfeit products and medical emergency preparation.

The FDA is accepting comments on the proposal for 120 days. 

Most medical devices distributed in the United States should carry an identification label to help identify and resolve problems associated with them, according to a statement issued the Food and Drug Administration on July 3.

The unique device identifier (UDI), an exclusive numeric or alphanumeric code, "has the potential to improve the quality of information in medical device adverse event reports, which will help the FDA identify product problems more quickly, better target recalls and improve patient safety," according to the statement.

FDA

In the proposed rule, the label will include an illustration of the device, the product name, its expiration date, reference and lot numbers, manufacturer information, as well as a bar code.

The UDI system is required by legislation passed by Congress in 2007 directing the agency to develop regulations establishing such a system, and the agency worked closely with industry, clinical groups, as well as patient and consumer groups, and has conducted four pilot studies in developing the proposed rule, according to the statement.

Implementation will be phased in, with the highest-risk medical devices labeled first. Low-risk devices will be exempt from some or all of the requirements and over-the-counter devices will be exempt, since they usually have a universal product code.

In addition to improving the accuracy of device-related adverse event reporting, the system is expected to expedite the resolution of device-related problems. The system also will address counterfeit products and medical emergency preparation.

The FDA is accepting comments on the proposal for 120 days. 

GAITHERSBURG, MD. – Evaluation of patients for adverse effects associated with a metal-on-metal hip implant should include an expedited physical exam with an orthopedic surgeon, routine x-rays, and both standard and specialized laboratory tests, a Food and Drug Administration advisory panel recommended at the end of a 2-day meeting on June 28.

Lab testing should include the standard blood tests, as well as measures of sedimentation rate and C-reactive protein level, and more sophisticated imaging with MRI or CT, if needed, according to the advisory panel of the FDA’s Orthopaedic and Rehabilitation Devices Panel, which met for 2 days to review the safety data on these devices.

Blood or serum tests for metal ions (cobalt and chromium, which have been elevated in some patients who have received metal-on-metal devices, and have been associated with device failures) also can be helpful, panelists said, although these tests are not universally available and how to use the results in determining the course of treatment is still unclear. They made similar recommendations on how to follow up symptomatic patients who have undergone hip resurfacing with a metal-on-metal device.

There was less consensus on how to follow patients who have received one of these devices but are asymptomatic; recommendations included obtaining a baseline evaluation, with an MRI (at least in patients who are part of a postmarketing study) and tests for metal ions so changes can be monitored and compared over time. One panelist called for longitudinal studies that collect this type of information at baseline, so that predictive factors for failure could be identified.

The panel was not asked to vote on any issues, only to provide advice, so that the agency can make recommendations on the safety of these devices to health care providers and patients. The agency usually follows the recommendations of its advisory panels.

Metal-on-metal hip resurfacing systems, which became popular for use in younger active patients who had healthier bone, include the femoral head with a metal covering, a femoral stem, and an acetabular component. The metal-on metal hip devices were thought to last longer. The proportion of procedures in which devices are used has declined in reaction to increased revision rates and reports of adverse events.

In May 2011, the FDA issued a public health communication regarding adverse event reports associated with these devices and subsequently ordered manufacturers to conduct post-marketing studies addressing the safety issues of their metal-on-metal total hip replacement devices. The FDA has recalled two metal-on-metal devices, including one in August 2010 for a higher than expected revision rate.

A review of metal-on metal implants in December 2011 conducted by the American Academy of Orthopaedic Surgeons concluded that the risk of revision was higher among patients who receive these implants for total hip arthroplasty and hip resurfacing than those who undergo this surgery using a different bearing. The AAOS review also found that larger femoral head components used in hip arthroplasty are associated with higher revision rates, which was also reported by speakers during the FDA panel meeting.

Alerts about local and soft tissue reactions and recommendations on metal ion testing and imaging of patients who have received one of these devices has been issued in the United Kingdom, Australia, and Canada.

When asked if they could describe any types of patients for whom the benefits of a metal-on-metal device for resurfacing or hip replacement outweigh the risks, panelists said that the decision should be up to the individual surgeon and that there might be some cases where this type of device may be useful. But the orthopedic surgeons on the panel said they rarely or never used metal-on metal implants because of these adverse event reports and availability of other options.

"I see no indication for which I would use a metal on metal [device] over any other technology," said the panel chair, Dr. William Rohr, an orthopedic surgeon who practices in Fort Bragg, Calif. He added that he had not seen any evidence indicating that the performance of the metal-on-metal devices was better than that of other options, and he considered any increased risk over the others available unacceptable, and pointed out gender differences, with women at risk of poorer outcomes

Members of FDA panels have been cleared of potential conflicts of interest; in some cases, they are given waivers but not at this meeting.

GAITHERSBURG, MD. – Evaluation of patients for adverse effects associated with a metal-on-metal hip implant should include an expedited physical exam with an orthopedic surgeon, routine x-rays, and both standard and specialized laboratory tests, a Food and Drug Administration advisory panel recommended at the end of a 2-day meeting on June 28.

Lab testing should include the standard blood tests, as well as measures of sedimentation rate and C-reactive protein level, and more sophisticated imaging with MRI or CT, if needed, according to the advisory panel of the FDA’s Orthopaedic and Rehabilitation Devices Panel, which met for 2 days to review the safety data on these devices.

Blood or serum tests for metal ions (cobalt and chromium, which have been elevated in some patients who have received metal-on-metal devices, and have been associated with device failures) also can be helpful, panelists said, although these tests are not universally available and how to use the results in determining the course of treatment is still unclear. They made similar recommendations on how to follow up symptomatic patients who have undergone hip resurfacing with a metal-on-metal device.

There was less consensus on how to follow patients who have received one of these devices but are asymptomatic; recommendations included obtaining a baseline evaluation, with an MRI (at least in patients who are part of a postmarketing study) and tests for metal ions so changes can be monitored and compared over time. One panelist called for longitudinal studies that collect this type of information at baseline, so that predictive factors for failure could be identified.

The panel was not asked to vote on any issues, only to provide advice, so that the agency can make recommendations on the safety of these devices to health care providers and patients. The agency usually follows the recommendations of its advisory panels.

Metal-on-metal hip resurfacing systems, which became popular for use in younger active patients who had healthier bone, include the femoral head with a metal covering, a femoral stem, and an acetabular component. The metal-on metal hip devices were thought to last longer. The proportion of procedures in which devices are used has declined in reaction to increased revision rates and reports of adverse events.

In May 2011, the FDA issued a public health communication regarding adverse event reports associated with these devices and subsequently ordered manufacturers to conduct post-marketing studies addressing the safety issues of their metal-on-metal total hip replacement devices. The FDA has recalled two metal-on-metal devices, including one in August 2010 for a higher than expected revision rate.

A review of metal-on metal implants in December 2011 conducted by the American Academy of Orthopaedic Surgeons concluded that the risk of revision was higher among patients who receive these implants for total hip arthroplasty and hip resurfacing than those who undergo this surgery using a different bearing. The AAOS review also found that larger femoral head components used in hip arthroplasty are associated with higher revision rates, which was also reported by speakers during the FDA panel meeting.

Alerts about local and soft tissue reactions and recommendations on metal ion testing and imaging of patients who have received one of these devices has been issued in the United Kingdom, Australia, and Canada.

When asked if they could describe any types of patients for whom the benefits of a metal-on-metal device for resurfacing or hip replacement outweigh the risks, panelists said that the decision should be up to the individual surgeon and that there might be some cases where this type of device may be useful. But the orthopedic surgeons on the panel said they rarely or never used metal-on metal implants because of these adverse event reports and availability of other options.

"I see no indication for which I would use a metal on metal [device] over any other technology," said the panel chair, Dr. William Rohr, an orthopedic surgeon who practices in Fort Bragg, Calif. He added that he had not seen any evidence indicating that the performance of the metal-on-metal devices was better than that of other options, and he considered any increased risk over the others available unacceptable, and pointed out gender differences, with women at risk of poorer outcomes

Members of FDA panels have been cleared of potential conflicts of interest; in some cases, they are given waivers but not at this meeting.

GAITHERSBURG, MD. – Evaluation of patients for adverse effects associated with a metal-on-metal hip implant should include an expedited physical exam with an orthopedic surgeon, routine x-rays, and both standard and specialized laboratory tests, a Food and Drug Administration advisory panel recommended at the end of a 2-day meeting on June 28.

Lab testing should include the standard blood tests, as well as measures of sedimentation rate and C-reactive protein level, and more sophisticated imaging with MRI or CT, if needed, according to the advisory panel of the FDA’s Orthopaedic and Rehabilitation Devices Panel, which met for 2 days to review the safety data on these devices.

Blood or serum tests for metal ions (cobalt and chromium, which have been elevated in some patients who have received metal-on-metal devices, and have been associated with device failures) also can be helpful, panelists said, although these tests are not universally available and how to use the results in determining the course of treatment is still unclear. They made similar recommendations on how to follow up symptomatic patients who have undergone hip resurfacing with a metal-on-metal device.

There was less consensus on how to follow patients who have received one of these devices but are asymptomatic; recommendations included obtaining a baseline evaluation, with an MRI (at least in patients who are part of a postmarketing study) and tests for metal ions so changes can be monitored and compared over time. One panelist called for longitudinal studies that collect this type of information at baseline, so that predictive factors for failure could be identified.

The panel was not asked to vote on any issues, only to provide advice, so that the agency can make recommendations on the safety of these devices to health care providers and patients. The agency usually follows the recommendations of its advisory panels.

Metal-on-metal hip resurfacing systems, which became popular for use in younger active patients who had healthier bone, include the femoral head with a metal covering, a femoral stem, and an acetabular component. The metal-on metal hip devices were thought to last longer. The proportion of procedures in which devices are used has declined in reaction to increased revision rates and reports of adverse events.

In May 2011, the FDA issued a public health communication regarding adverse event reports associated with these devices and subsequently ordered manufacturers to conduct post-marketing studies addressing the safety issues of their metal-on-metal total hip replacement devices. The FDA has recalled two metal-on-metal devices, including one in August 2010 for a higher than expected revision rate.

A review of metal-on metal implants in December 2011 conducted by the American Academy of Orthopaedic Surgeons concluded that the risk of revision was higher among patients who receive these implants for total hip arthroplasty and hip resurfacing than those who undergo this surgery using a different bearing. The AAOS review also found that larger femoral head components used in hip arthroplasty are associated with higher revision rates, which was also reported by speakers during the FDA panel meeting.

Alerts about local and soft tissue reactions and recommendations on metal ion testing and imaging of patients who have received one of these devices has been issued in the United Kingdom, Australia, and Canada.

When asked if they could describe any types of patients for whom the benefits of a metal-on-metal device for resurfacing or hip replacement outweigh the risks, panelists said that the decision should be up to the individual surgeon and that there might be some cases where this type of device may be useful. But the orthopedic surgeons on the panel said they rarely or never used metal-on metal implants because of these adverse event reports and availability of other options.

"I see no indication for which I would use a metal on metal [device] over any other technology," said the panel chair, Dr. William Rohr, an orthopedic surgeon who practices in Fort Bragg, Calif. He added that he had not seen any evidence indicating that the performance of the metal-on-metal devices was better than that of other options, and he considered any increased risk over the others available unacceptable, and pointed out gender differences, with women at risk of poorer outcomes

Members of FDA panels have been cleared of potential conflicts of interest; in some cases, they are given waivers but not at this meeting.