Elizabeth Mechcatie

SILVER SPRING, MD. — Reducing preventable injuries from medication errors, misuse, and abuse is the goal of an initiative being launched by the Food and Drug Administration, agency officials announced at a briefing.

The Safe Use Initiative is intended to “reduce preventable harm by identifying specific, preventable medication risks and developing, implementing, and evaluating cross-sector interventions with partners who are committed to safe medication use,” according to the FDA. In addition to health care professionals, partners will include federal agencies, professional societies, pharmacies, hospitals, and manufacturers, as well as patients, caregivers, and consumers.

Drugs, drug classes, and therapeutic situations associated with preventable harm will be identified as part of the initiative.

The initiative will use measures of success to evaluate the impact of those interventions, Dr. Margaret Hamburg, FDA Commissioner, said during the briefing. Each year, adverse events from drug use result in more than 4 million visits to emergency rooms, physicians' offices, and outpatient facilities, and 117,000 hospitalizations, she said.

As many as half of all medication injuries—including dosing errors, mix-ups during drug administration, and unintentional misuse of the medication—could be prevented with currently available information about the medication, Dr. Hamburg added.

At the briefing, Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, who will be spearheading the initiative, distinguished between the events targeted by the initiative and inherent medication risks that are not preventable, such as side effects of chemotherapy.

Dr. Woodcock said that the agency has discussed the initiative with physicians' and nurses' professional groups, and will seek input from the health care community and the public to determine what they perceive to be the biggest problems. Proposed interventions will be specific to a particular problem, she said. The agency also announced a new draft guidance document on delivery devices for over-the-counter liquid drug products for companies that manufacture, market, or distribute medications such as elixirs, suspensions, and syrups, which are packaged with calibrated cups, droppers, syringes, or other dosage delivery devices.

The draft guidance addresses “ongoing safety concerns about the serious potential for accidental drug overdoses of OTC liquid drug products that can result from the use of dosage delivery devices with markings that are inconsistent or incompatible with the labeled dosage directions for OTC drug products,” according to the document published in the Federal Register on Nov. 4.

SILVER SPRING, MD. — Reducing preventable injuries from medication errors, misuse, and abuse is the goal of an initiative being launched by the Food and Drug Administration, agency officials announced at a briefing.

The Safe Use Initiative is intended to “reduce preventable harm by identifying specific, preventable medication risks and developing, implementing, and evaluating cross-sector interventions with partners who are committed to safe medication use,” according to the FDA. In addition to health care professionals, partners will include federal agencies, professional societies, pharmacies, hospitals, and manufacturers, as well as patients, caregivers, and consumers.

Drugs, drug classes, and therapeutic situations associated with preventable harm will be identified as part of the initiative.

The initiative will use measures of success to evaluate the impact of those interventions, Dr. Margaret Hamburg, FDA Commissioner, said during the briefing. Each year, adverse events from drug use result in more than 4 million visits to emergency rooms, physicians' offices, and outpatient facilities, and 117,000 hospitalizations, she said.

As many as half of all medication injuries—including dosing errors, mix-ups during drug administration, and unintentional misuse of the medication—could be prevented with currently available information about the medication, Dr. Hamburg added.

At the briefing, Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, who will be spearheading the initiative, distinguished between the events targeted by the initiative and inherent medication risks that are not preventable, such as side effects of chemotherapy.

Dr. Woodcock said that the agency has discussed the initiative with physicians' and nurses' professional groups, and will seek input from the health care community and the public to determine what they perceive to be the biggest problems. Proposed interventions will be specific to a particular problem, she said. The agency also announced a new draft guidance document on delivery devices for over-the-counter liquid drug products for companies that manufacture, market, or distribute medications such as elixirs, suspensions, and syrups, which are packaged with calibrated cups, droppers, syringes, or other dosage delivery devices.

The draft guidance addresses “ongoing safety concerns about the serious potential for accidental drug overdoses of OTC liquid drug products that can result from the use of dosage delivery devices with markings that are inconsistent or incompatible with the labeled dosage directions for OTC drug products,” according to the document published in the Federal Register on Nov. 4.

SILVER SPRING, MD. — Reducing preventable injuries from medication errors, misuse, and abuse is the goal of an initiative being launched by the Food and Drug Administration, agency officials announced at a briefing.

The Safe Use Initiative is intended to “reduce preventable harm by identifying specific, preventable medication risks and developing, implementing, and evaluating cross-sector interventions with partners who are committed to safe medication use,” according to the FDA. In addition to health care professionals, partners will include federal agencies, professional societies, pharmacies, hospitals, and manufacturers, as well as patients, caregivers, and consumers.

Drugs, drug classes, and therapeutic situations associated with preventable harm will be identified as part of the initiative.

The initiative will use measures of success to evaluate the impact of those interventions, Dr. Margaret Hamburg, FDA Commissioner, said during the briefing. Each year, adverse events from drug use result in more than 4 million visits to emergency rooms, physicians' offices, and outpatient facilities, and 117,000 hospitalizations, she said.

As many as half of all medication injuries—including dosing errors, mix-ups during drug administration, and unintentional misuse of the medication—could be prevented with currently available information about the medication, Dr. Hamburg added.

At the briefing, Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, who will be spearheading the initiative, distinguished between the events targeted by the initiative and inherent medication risks that are not preventable, such as side effects of chemotherapy.

Dr. Woodcock said that the agency has discussed the initiative with physicians' and nurses' professional groups, and will seek input from the health care community and the public to determine what they perceive to be the biggest problems. Proposed interventions will be specific to a particular problem, she said. The agency also announced a new draft guidance document on delivery devices for over-the-counter liquid drug products for companies that manufacture, market, or distribute medications such as elixirs, suspensions, and syrups, which are packaged with calibrated cups, droppers, syringes, or other dosage delivery devices.

The draft guidance addresses “ongoing safety concerns about the serious potential for accidental drug overdoses of OTC liquid drug products that can result from the use of dosage delivery devices with markings that are inconsistent or incompatible with the labeled dosage directions for OTC drug products,” according to the document published in the Federal Register on Nov. 4.

Counterfeit versions of Alli, the over-the-counter formulation of the lipase inhibitor orlistat, contain sibutramine another weight loss agent, and could be “potentially harmful” for consumers, the Food and Drug Administration announced last month.

A statement posted on the agency's MedWatch site said orlistat manufacturer GlaxoSmithKline (GSK) had identified counterfeit versions of Alli 60-mgcapsules in the 120-count refill kit that do not contain orlistat. The counterfeit products contain sibutramine, a controlled substance that is marketed as Meridia by Abbott Laboratories. Sibutramine's therapeutic effects result from norepinephrine, serotonin, and dopamine reuptake inhibitionoaccording to the label.

Suspected reports of counterfeit Alli products were first made in December 2009. GSK has determined that the counterfeit products have been sold over the Internet and that there is no evidence the counterfeit product has been sold through retail stores or other channels.

The differences between the counterfeit product and the real product include the lot code, packaging, and expiration date: The counterfeit product does not have a “Lot” code on the outer cardboard packaging and the plastic bottle has a slightly taller and wider cap, with “coarser ribbing” than the authentic product.

In addition, the expiration date on the counterfeit product includes the month day and year—such as 06162010–while the authentic product includes the month and year only—such as 06/10. The foil that seals the opening of the counterfeit bottle has no printed words, but this safety seal on the authentic product seal is printed with “SEALED for YOUR PROTECTION.” Finally, the counterfeit product contains a white powder, while the authentic capsules contain small white pellets.

Prescription orlistat is marketed as Xenical, and is available in a 120-mg dose. Alli, 60-mg, was approved for over the counter use in 2007.

People who believe they have a counterfeit Alli product should contact the FDA's Office of Criminal Investigations at 800-551-3989 or www.fda.gov/OCImakewww.fda.gov/medwatch

Counterfeit versions of Alli, the over-the-counter formulation of the lipase inhibitor orlistat, contain sibutramine another weight loss agent, and could be “potentially harmful” for consumers, the Food and Drug Administration announced last month.

A statement posted on the agency's MedWatch site said orlistat manufacturer GlaxoSmithKline (GSK) had identified counterfeit versions of Alli 60-mgcapsules in the 120-count refill kit that do not contain orlistat. The counterfeit products contain sibutramine, a controlled substance that is marketed as Meridia by Abbott Laboratories. Sibutramine's therapeutic effects result from norepinephrine, serotonin, and dopamine reuptake inhibitionoaccording to the label.

Suspected reports of counterfeit Alli products were first made in December 2009. GSK has determined that the counterfeit products have been sold over the Internet and that there is no evidence the counterfeit product has been sold through retail stores or other channels.

The differences between the counterfeit product and the real product include the lot code, packaging, and expiration date: The counterfeit product does not have a “Lot” code on the outer cardboard packaging and the plastic bottle has a slightly taller and wider cap, with “coarser ribbing” than the authentic product.

In addition, the expiration date on the counterfeit product includes the month day and year—such as 06162010–while the authentic product includes the month and year only—such as 06/10. The foil that seals the opening of the counterfeit bottle has no printed words, but this safety seal on the authentic product seal is printed with “SEALED for YOUR PROTECTION.” Finally, the counterfeit product contains a white powder, while the authentic capsules contain small white pellets.

Prescription orlistat is marketed as Xenical, and is available in a 120-mg dose. Alli, 60-mg, was approved for over the counter use in 2007.

People who believe they have a counterfeit Alli product should contact the FDA's Office of Criminal Investigations at 800-551-3989 or www.fda.gov/OCImakewww.fda.gov/medwatch

Counterfeit versions of Alli, the over-the-counter formulation of the lipase inhibitor orlistat, contain sibutramine another weight loss agent, and could be “potentially harmful” for consumers, the Food and Drug Administration announced last month.

A statement posted on the agency's MedWatch site said orlistat manufacturer GlaxoSmithKline (GSK) had identified counterfeit versions of Alli 60-mgcapsules in the 120-count refill kit that do not contain orlistat. The counterfeit products contain sibutramine, a controlled substance that is marketed as Meridia by Abbott Laboratories. Sibutramine's therapeutic effects result from norepinephrine, serotonin, and dopamine reuptake inhibitionoaccording to the label.

Suspected reports of counterfeit Alli products were first made in December 2009. GSK has determined that the counterfeit products have been sold over the Internet and that there is no evidence the counterfeit product has been sold through retail stores or other channels.

The differences between the counterfeit product and the real product include the lot code, packaging, and expiration date: The counterfeit product does not have a “Lot” code on the outer cardboard packaging and the plastic bottle has a slightly taller and wider cap, with “coarser ribbing” than the authentic product.

In addition, the expiration date on the counterfeit product includes the month day and year—such as 06162010–while the authentic product includes the month and year only—such as 06/10. The foil that seals the opening of the counterfeit bottle has no printed words, but this safety seal on the authentic product seal is printed with “SEALED for YOUR PROTECTION.” Finally, the counterfeit product contains a white powder, while the authentic capsules contain small white pellets.

Prescription orlistat is marketed as Xenical, and is available in a 120-mg dose. Alli, 60-mg, was approved for over the counter use in 2007.

People who believe they have a counterfeit Alli product should contact the FDA's Office of Criminal Investigations at 800-551-3989 or www.fda.gov/OCImakewww.fda.gov/medwatch

Treatment with the Spiriva HandiHaler, which contains a dry powder formulation of the anticholinergic tiotropium, does not appear to be associated with an increased risk of stroke, myocardial infarction, or cardiovascular death in patients with chronic obstructive pulmonary disease, the Food and Drug Administration announced.

The FDA has now completed its safety review of this product “and believes the available data do not support an association between the use of Spiriva HandiHaler and an increased risk for these serious adverse events,” according to an agency statement.

The Spiriva HandiHaler, marketed by Boehringer Ingelheim and Pfizer, was approved in 2004 for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. It is administered once daily.

The FDA has been conducting a safety review of the Spiriva HandiHaler since the manufacturer submitted data suggesting that treatment with tiotropium was tied to a small increased risk of stroke compared to placebo (2 cases per 1,000 treated patients). It announced the review in March 2008. In October 2008, the agency issued a statement about two published studies that suggested an increased risk of stroke, MI, and death in patients treated with tiotropium.

The latest FDA statement said that a 4-year study comparing treatment with the Spiriva HandiHaler to placebo in almost 6,000 patients with COPD found no increase in the risk of these outcomes in the treatment arm.

The study was reviewed by the FDA's Pulmonary-Allergy Drugs Advisory Committee in November 2009. In a near unanimous vote, the panel agreed that the data adequately resolve the potential safety concerns for stroke and adverse cardiovascular outcomes associated with this product.

Treatment with the Spiriva HandiHaler, which contains a dry powder formulation of the anticholinergic tiotropium, does not appear to be associated with an increased risk of stroke, myocardial infarction, or cardiovascular death in patients with chronic obstructive pulmonary disease, the Food and Drug Administration announced.

The FDA has now completed its safety review of this product “and believes the available data do not support an association between the use of Spiriva HandiHaler and an increased risk for these serious adverse events,” according to an agency statement.

The Spiriva HandiHaler, marketed by Boehringer Ingelheim and Pfizer, was approved in 2004 for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. It is administered once daily.

The FDA has been conducting a safety review of the Spiriva HandiHaler since the manufacturer submitted data suggesting that treatment with tiotropium was tied to a small increased risk of stroke compared to placebo (2 cases per 1,000 treated patients). It announced the review in March 2008. In October 2008, the agency issued a statement about two published studies that suggested an increased risk of stroke, MI, and death in patients treated with tiotropium.

The latest FDA statement said that a 4-year study comparing treatment with the Spiriva HandiHaler to placebo in almost 6,000 patients with COPD found no increase in the risk of these outcomes in the treatment arm.

The study was reviewed by the FDA's Pulmonary-Allergy Drugs Advisory Committee in November 2009. In a near unanimous vote, the panel agreed that the data adequately resolve the potential safety concerns for stroke and adverse cardiovascular outcomes associated with this product.

Treatment with the Spiriva HandiHaler, which contains a dry powder formulation of the anticholinergic tiotropium, does not appear to be associated with an increased risk of stroke, myocardial infarction, or cardiovascular death in patients with chronic obstructive pulmonary disease, the Food and Drug Administration announced.

The FDA has now completed its safety review of this product “and believes the available data do not support an association between the use of Spiriva HandiHaler and an increased risk for these serious adverse events,” according to an agency statement.

The Spiriva HandiHaler, marketed by Boehringer Ingelheim and Pfizer, was approved in 2004 for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. It is administered once daily.

The FDA has been conducting a safety review of the Spiriva HandiHaler since the manufacturer submitted data suggesting that treatment with tiotropium was tied to a small increased risk of stroke compared to placebo (2 cases per 1,000 treated patients). It announced the review in March 2008. In October 2008, the agency issued a statement about two published studies that suggested an increased risk of stroke, MI, and death in patients treated with tiotropium.

The latest FDA statement said that a 4-year study comparing treatment with the Spiriva HandiHaler to placebo in almost 6,000 patients with COPD found no increase in the risk of these outcomes in the treatment arm.

The study was reviewed by the FDA's Pulmonary-Allergy Drugs Advisory Committee in November 2009. In a near unanimous vote, the panel agreed that the data adequately resolve the potential safety concerns for stroke and adverse cardiovascular outcomes associated with this product.

Major Finding: Adults undergoing screening colonoscopy within 10 years of a previous colonoscopy had a significantly lower risk of having a left-sided advanced neoplasm detected, but their risk of right-sided neoplasms was not reduced.

Data Source: A population-based study of 3,287 adults aged 55 and older presenting for a screening colonoscopy at 33 German gastroenterology practices between May 1, 2005, and Dec. 31, 2007.

Disclosures: Study partly supported by the Central Research Institute of Ambulatory Health Care in Germany (Berlin).

The risk of left-sided advanced colorectal neoplasms was reduced by 67% within 10 years of having a screening colonoscopy, but there was no reduction in risk of right-sided neoplasms in a German community-based study of more than 3,000 people.

“Although a strong protective effect of colonoscopy from colorectal neoplasms has been established through previous studies, our results add to the evidence that this effect is much stronger in, if not confined to, the left colon and rectum, at least in the community setting,” concluded Dr. Hermann Brenner and his associates of the division of clinical epidemiology and aging research at the German Cancer Research Center, Heidelberg.

The lack of an effect in the right colon could “be overcome to some extent by enhanced training of endoscopists, by enhanced measures of quality assurance, and by development of technology that enhances inspection of the right colon,” they added (J. Natl. Cancer Inst. 2009;102:1–7).

The study included 3,287 people older than 55 years undergoing a screening colonoscopy at 33 gastroenterology practices in Saarland (Germany) between May 1, 2005, and Dec. 31, 2007. The researchers compared the prevalence of colorectal cancer and advanced adenomas (combined as “advanced colorectal neoplasm”) among those who reported having had a colonoscopy within the previous decade to the prevalence among those who said they had not had a colonoscopy previously.

An advanced colorectal neoplasm was found in 308 of the 2,701 participants (11.4%) who had not had a colonoscopy, compared with 36 of the 586 participants (6.1%) who had had a colonoscopy 1–10 years earlier. One case of colorectal cancer occurred in those who had undergone colonoscopy, and 41 cases in those who had not.

After adjustment for age, sex, and family history of colorectal cancer, the prevalence ratio of colorectal cancer was 0.52 overall. “However, in site-specific analyses, previous colonoscopy was strongly and inversely associated with prevalence of advanced neoplasia in the left-sided colon and rectum but not with prevalence of advanced neoplasia in the right-sided colon,” they reported.

The adjusted prevalence ratios were as follows: 0.99 for the cecum and ascending colon, 1.21 for the hepatic flexure and transverse colon, 0.36 for the splenic flexure and descending colon, 0.29 for the sigmoid colon, and 0.07 for the rectum.

Possible reasons for the lack of an effect of previous colonoscopy on the prevalence of right-sided neoplasms include incomplete colonoscopies or worse bowel preparation in the right colon. There also could be a higher proportion of adenomas in the right colon that are sessile and flat, and therefore easier to miss.

The results were similar to the odds ratio of deaths in a community-based study in Canada that used administrative claims data (Ann. Intern. Med. 2009;150:1–8). In that study, having a colonoscopy within 6 months of a diagnosis was associated with about a 40% lower risk of colorectal cancer mortality. This benefit also was “restricted essentially to left-sided colorectal cancers.”

In an editorial, the lead author of that study, Dr. Nancy Baxter of St. Michael's Hospital, Toronto, referred to some limitations of the German study, but pointed out that the results were “remarkably consistent with a number of recently published studies, all of which demonstrate the overall effectiveness of colonoscopy for reducing colorectal cancer incidence and mortality, but with a marked variance in effectiveness for proximal and distal cancers” (J. Natl. Cancer Inst. 2009;102:70–1).

My Take

Results Are a Cause for Concern

We must be concerned about these results because several studies in several settings have reported that protection from colonoscopy in the right colon is not as good as it is in the left colon, and we don't understand the reasons behind these differences. The only study done in the United States was a study of the California MediCal population; it showed the same trend, but differed from the German and Canadian studies in that there was still some protection in the right colon (about 60% in men; only about 20% in women).

There are two categories of explanations for poor right colon protection from colonoscopy. One is that differing biologic factors between right and left colon cancers prevent us from achieving effective cancer prevention. We know that microsatellite instability (MSI) is more common in right-sided cancers and in cancers occurring after colonoscopy, or so-called interval cancers. MSI can cause tumors to go through the polyp-cancer sequence faster. Similarly, the CpG island methylator phenotype (CIMP) is more common in interval cancers. The second category of explanations is technical issues in colonoscopy performance that may affect right colon detection, including failed cecal intubation, poor preparation (which affects the right colon preferentially), and flat lesions and serrated polyps, both of which are more common in the right colon and easier to miss at colonoscopy, compared with traditional adenomas.

My bias is that we can probably correct a significant portion of this problem by improving colonoscopy performance. First, everyone should use split-dose bowel preparations. There are now 10 randomized, controlled trials showing that splitting the prep—giving half of it on the day of the procedure—improves the preparation in the ascending colon. Second, we need all colonoscopists to photodocument the cecum. Finally, increased awareness and perhaps special training are needed to improve detection of flat and serrated polyps.

We have a lot of information that adenoma detection is operator-dependent and varies dramatically between endoscopists. We need information about whether interval cancers are clustering among individual endoscopists, as this would provide a strong hint about whether my bias that we can fix this problem is correct. We must reduce the operator dependency of colonoscopy. It's not good when a procedure that is so important for prevention of a common cancer is operator dependent. It's a flaw in the strategy.

DR. DOUGLAS K. REX is distinguished professor of medicine at Indiana University, Indianapolis.

Vitals

Major Finding: Adults undergoing screening colonoscopy within 10 years of a previous colonoscopy had a significantly lower risk of having a left-sided advanced neoplasm detected, but their risk of right-sided neoplasms was not reduced.

Data Source: A population-based study of 3,287 adults aged 55 and older presenting for a screening colonoscopy at 33 German gastroenterology practices between May 1, 2005, and Dec. 31, 2007.

Disclosures: Study partly supported by the Central Research Institute of Ambulatory Health Care in Germany (Berlin).

The risk of left-sided advanced colorectal neoplasms was reduced by 67% within 10 years of having a screening colonoscopy, but there was no reduction in risk of right-sided neoplasms in a German community-based study of more than 3,000 people.

“Although a strong protective effect of colonoscopy from colorectal neoplasms has been established through previous studies, our results add to the evidence that this effect is much stronger in, if not confined to, the left colon and rectum, at least in the community setting,” concluded Dr. Hermann Brenner and his associates of the division of clinical epidemiology and aging research at the German Cancer Research Center, Heidelberg.

The lack of an effect in the right colon could “be overcome to some extent by enhanced training of endoscopists, by enhanced measures of quality assurance, and by development of technology that enhances inspection of the right colon,” they added (J. Natl. Cancer Inst. 2009;102:1–7).

The study included 3,287 people older than 55 years undergoing a screening colonoscopy at 33 gastroenterology practices in Saarland (Germany) between May 1, 2005, and Dec. 31, 2007. The researchers compared the prevalence of colorectal cancer and advanced adenomas (combined as “advanced colorectal neoplasm”) among those who reported having had a colonoscopy within the previous decade to the prevalence among those who said they had not had a colonoscopy previously.

An advanced colorectal neoplasm was found in 308 of the 2,701 participants (11.4%) who had not had a colonoscopy, compared with 36 of the 586 participants (6.1%) who had had a colonoscopy 1–10 years earlier. One case of colorectal cancer occurred in those who had undergone colonoscopy, and 41 cases in those who had not.

After adjustment for age, sex, and family history of colorectal cancer, the prevalence ratio of colorectal cancer was 0.52 overall. “However, in site-specific analyses, previous colonoscopy was strongly and inversely associated with prevalence of advanced neoplasia in the left-sided colon and rectum but not with prevalence of advanced neoplasia in the right-sided colon,” they reported.

The adjusted prevalence ratios were as follows: 0.99 for the cecum and ascending colon, 1.21 for the hepatic flexure and transverse colon, 0.36 for the splenic flexure and descending colon, 0.29 for the sigmoid colon, and 0.07 for the rectum.

Possible reasons for the lack of an effect of previous colonoscopy on the prevalence of right-sided neoplasms include incomplete colonoscopies or worse bowel preparation in the right colon. There also could be a higher proportion of adenomas in the right colon that are sessile and flat, and therefore easier to miss.

The results were similar to the odds ratio of deaths in a community-based study in Canada that used administrative claims data (Ann. Intern. Med. 2009;150:1–8). In that study, having a colonoscopy within 6 months of a diagnosis was associated with about a 40% lower risk of colorectal cancer mortality. This benefit also was “restricted essentially to left-sided colorectal cancers.”

In an editorial, the lead author of that study, Dr. Nancy Baxter of St. Michael's Hospital, Toronto, referred to some limitations of the German study, but pointed out that the results were “remarkably consistent with a number of recently published studies, all of which demonstrate the overall effectiveness of colonoscopy for reducing colorectal cancer incidence and mortality, but with a marked variance in effectiveness for proximal and distal cancers” (J. Natl. Cancer Inst. 2009;102:70–1).

My Take

Results Are a Cause for Concern

We must be concerned about these results because several studies in several settings have reported that protection from colonoscopy in the right colon is not as good as it is in the left colon, and we don't understand the reasons behind these differences. The only study done in the United States was a study of the California MediCal population; it showed the same trend, but differed from the German and Canadian studies in that there was still some protection in the right colon (about 60% in men; only about 20% in women).

There are two categories of explanations for poor right colon protection from colonoscopy. One is that differing biologic factors between right and left colon cancers prevent us from achieving effective cancer prevention. We know that microsatellite instability (MSI) is more common in right-sided cancers and in cancers occurring after colonoscopy, or so-called interval cancers. MSI can cause tumors to go through the polyp-cancer sequence faster. Similarly, the CpG island methylator phenotype (CIMP) is more common in interval cancers. The second category of explanations is technical issues in colonoscopy performance that may affect right colon detection, including failed cecal intubation, poor preparation (which affects the right colon preferentially), and flat lesions and serrated polyps, both of which are more common in the right colon and easier to miss at colonoscopy, compared with traditional adenomas.

My bias is that we can probably correct a significant portion of this problem by improving colonoscopy performance. First, everyone should use split-dose bowel preparations. There are now 10 randomized, controlled trials showing that splitting the prep—giving half of it on the day of the procedure—improves the preparation in the ascending colon. Second, we need all colonoscopists to photodocument the cecum. Finally, increased awareness and perhaps special training are needed to improve detection of flat and serrated polyps.

We have a lot of information that adenoma detection is operator-dependent and varies dramatically between endoscopists. We need information about whether interval cancers are clustering among individual endoscopists, as this would provide a strong hint about whether my bias that we can fix this problem is correct. We must reduce the operator dependency of colonoscopy. It's not good when a procedure that is so important for prevention of a common cancer is operator dependent. It's a flaw in the strategy.

DR. DOUGLAS K. REX is distinguished professor of medicine at Indiana University, Indianapolis.

Vitals

Major Finding: Adults undergoing screening colonoscopy within 10 years of a previous colonoscopy had a significantly lower risk of having a left-sided advanced neoplasm detected, but their risk of right-sided neoplasms was not reduced.

Data Source: A population-based study of 3,287 adults aged 55 and older presenting for a screening colonoscopy at 33 German gastroenterology practices between May 1, 2005, and Dec. 31, 2007.

Disclosures: Study partly supported by the Central Research Institute of Ambulatory Health Care in Germany (Berlin).

The risk of left-sided advanced colorectal neoplasms was reduced by 67% within 10 years of having a screening colonoscopy, but there was no reduction in risk of right-sided neoplasms in a German community-based study of more than 3,000 people.

“Although a strong protective effect of colonoscopy from colorectal neoplasms has been established through previous studies, our results add to the evidence that this effect is much stronger in, if not confined to, the left colon and rectum, at least in the community setting,” concluded Dr. Hermann Brenner and his associates of the division of clinical epidemiology and aging research at the German Cancer Research Center, Heidelberg.

The lack of an effect in the right colon could “be overcome to some extent by enhanced training of endoscopists, by enhanced measures of quality assurance, and by development of technology that enhances inspection of the right colon,” they added (J. Natl. Cancer Inst. 2009;102:1–7).

The study included 3,287 people older than 55 years undergoing a screening colonoscopy at 33 gastroenterology practices in Saarland (Germany) between May 1, 2005, and Dec. 31, 2007. The researchers compared the prevalence of colorectal cancer and advanced adenomas (combined as “advanced colorectal neoplasm”) among those who reported having had a colonoscopy within the previous decade to the prevalence among those who said they had not had a colonoscopy previously.

An advanced colorectal neoplasm was found in 308 of the 2,701 participants (11.4%) who had not had a colonoscopy, compared with 36 of the 586 participants (6.1%) who had had a colonoscopy 1–10 years earlier. One case of colorectal cancer occurred in those who had undergone colonoscopy, and 41 cases in those who had not.

After adjustment for age, sex, and family history of colorectal cancer, the prevalence ratio of colorectal cancer was 0.52 overall. “However, in site-specific analyses, previous colonoscopy was strongly and inversely associated with prevalence of advanced neoplasia in the left-sided colon and rectum but not with prevalence of advanced neoplasia in the right-sided colon,” they reported.

The adjusted prevalence ratios were as follows: 0.99 for the cecum and ascending colon, 1.21 for the hepatic flexure and transverse colon, 0.36 for the splenic flexure and descending colon, 0.29 for the sigmoid colon, and 0.07 for the rectum.

Possible reasons for the lack of an effect of previous colonoscopy on the prevalence of right-sided neoplasms include incomplete colonoscopies or worse bowel preparation in the right colon. There also could be a higher proportion of adenomas in the right colon that are sessile and flat, and therefore easier to miss.

The results were similar to the odds ratio of deaths in a community-based study in Canada that used administrative claims data (Ann. Intern. Med. 2009;150:1–8). In that study, having a colonoscopy within 6 months of a diagnosis was associated with about a 40% lower risk of colorectal cancer mortality. This benefit also was “restricted essentially to left-sided colorectal cancers.”

In an editorial, the lead author of that study, Dr. Nancy Baxter of St. Michael's Hospital, Toronto, referred to some limitations of the German study, but pointed out that the results were “remarkably consistent with a number of recently published studies, all of which demonstrate the overall effectiveness of colonoscopy for reducing colorectal cancer incidence and mortality, but with a marked variance in effectiveness for proximal and distal cancers” (J. Natl. Cancer Inst. 2009;102:70–1).

My Take

Results Are a Cause for Concern

We must be concerned about these results because several studies in several settings have reported that protection from colonoscopy in the right colon is not as good as it is in the left colon, and we don't understand the reasons behind these differences. The only study done in the United States was a study of the California MediCal population; it showed the same trend, but differed from the German and Canadian studies in that there was still some protection in the right colon (about 60% in men; only about 20% in women).

There are two categories of explanations for poor right colon protection from colonoscopy. One is that differing biologic factors between right and left colon cancers prevent us from achieving effective cancer prevention. We know that microsatellite instability (MSI) is more common in right-sided cancers and in cancers occurring after colonoscopy, or so-called interval cancers. MSI can cause tumors to go through the polyp-cancer sequence faster. Similarly, the CpG island methylator phenotype (CIMP) is more common in interval cancers. The second category of explanations is technical issues in colonoscopy performance that may affect right colon detection, including failed cecal intubation, poor preparation (which affects the right colon preferentially), and flat lesions and serrated polyps, both of which are more common in the right colon and easier to miss at colonoscopy, compared with traditional adenomas.

My bias is that we can probably correct a significant portion of this problem by improving colonoscopy performance. First, everyone should use split-dose bowel preparations. There are now 10 randomized, controlled trials showing that splitting the prep—giving half of it on the day of the procedure—improves the preparation in the ascending colon. Second, we need all colonoscopists to photodocument the cecum. Finally, increased awareness and perhaps special training are needed to improve detection of flat and serrated polyps.

We have a lot of information that adenoma detection is operator-dependent and varies dramatically between endoscopists. We need information about whether interval cancers are clustering among individual endoscopists, as this would provide a strong hint about whether my bias that we can fix this problem is correct. We must reduce the operator dependency of colonoscopy. It's not good when a procedure that is so important for prevention of a common cancer is operator dependent. It's a flaw in the strategy.

DR. DOUGLAS K. REX is distinguished professor of medicine at Indiana University, Indianapolis.

Vitals

COLLEGE PARK, MD. — Special training in safe prescription of long-acting opioid drugs, as well as the use of patient-prescriber agreements, could be required to earn federal approval to prescribe such products, under proposals discussed by an industry working group.

At a public meeting held by the Food and Drug Administration, the working group presented those and other options as part of an initiative to develop a class-wide risk evaluation and mitigation strategy (REMS) for long-acting opioid drugs.

In February 2009, the FDA informed manufacturers of long-acting opioid products that they would have to develop a single REMS for the drug class. The FDA wants to reduce abuse, misuse, overdose, and addiction associated with the use of the products, and to ensure that their benefits outweigh their risks.

Under one element of the plan under consideration, clinicians seeking Drug Enforcement Agency registration to prescribe schedule II controlled substances would be required to certify that they were trained to safely prescribe and choose the appropriate patients for the drugs. Currently, a physician can obtain DEA registration without a training requirement. Giving the DEA such authority would require an act of Congress, according to one of the industry working group representatives.

Voluntary programs could be developed, possibly with medical specialty societies, while legislative efforts are underway, the working group noted.

Requiring such training raises the concern that some physicians would opt out of training—thus reducing access to the drugs for patients who need them, said Dr. John Jenkins, director of the Office of New Drugs, in the FDA's Center for Drug Evaluation and Research.

The REMS program's goals are to ensure that the drugs' benefits exceed their risks, while providing access for patients who need them, Dr. Jenkins noted during a press briefing after the meeting.

The drugs to be included in the REMS are brand-name and generic products that contain fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Among the problems associated with those products include their use in patients who are nonopioid tolerant or otherwise inappropriately selected, as well as misuse and abuse of the drugs.

Dr. Jenkins cited the example of pain treatment with methadone—which, when taken too frequently, can result rapidly in an overdose.

Short-acting opioid products were not discussed, but meeting participants expressed concern that an effective REMS for long-acting products could shift misuse and abuse to shorter-acting agents.

The working group also proposed these ideas:

▸ A patient-prescriber agreement. This would serve as a tool to facilitate discussion between the physician and patient.

▸ A medication information sheet.

▸ Metrics to assess the impact of the REMS. There should be a measure to determine whether the REMS impedes patients' access to appropriate medication, the working group noted.

The working group made no definitive conclusions at the meeting and has not developed a final plan for the REMS.

Dr. Jenkins said he couldn't predict when the REMS would be finalized. But an FDA advisory panel will meet in the spring to discuss the elements of the proposed REMS, to solicit advice from experts, and to hear public comment, he added. Until a final REMS is approved, Dr. Jenkins said, the FDA will require an interim REMS for any product in this drug class.

My Take

Pain Treatment Could Be Restricted

Requiring physicians to undergo training in order to prescribe opioids would be a major impediment to the care of patients. Most of the physicians I have spoken to say they would not take such training and would instead simply stop prescribing the related drugs. The problem is that most of us have a few patients requiring long-term narcotics, but just a few, and most narcotic use in rheumatology is short term or limited long-term use (e.g., 20 tablets for 3-6 months).

The patient-prescriber agreement is important but is really only needed for patients using continuous long-term narcotics. The medication information sheet is a good idea, but what is the role of the pharmacist? In many states, the pharmacist has access to electronic records of narcotic prescriptions. Shouldn't they have the responsibility of notifying physicians of misuse?

It seems to me that the imposition of training and compulsory use of forms would not reduce the risk of addiction or improve detection of abuse, but it would add another layer of rules and make it more difficult to practice medicine and provide appropriate patient care.

ROY ALTMAN, M.D., is professor of rheumatology and immunology at the University of California Los Angeles. Dr. Altman reported having financial relationships with numerous pharmaceutical companies.

Vitals

COLLEGE PARK, MD. — Special training in safe prescription of long-acting opioid drugs, as well as the use of patient-prescriber agreements, could be required to earn federal approval to prescribe such products, under proposals discussed by an industry working group.

At a public meeting held by the Food and Drug Administration, the working group presented those and other options as part of an initiative to develop a class-wide risk evaluation and mitigation strategy (REMS) for long-acting opioid drugs.

In February 2009, the FDA informed manufacturers of long-acting opioid products that they would have to develop a single REMS for the drug class. The FDA wants to reduce abuse, misuse, overdose, and addiction associated with the use of the products, and to ensure that their benefits outweigh their risks.

Under one element of the plan under consideration, clinicians seeking Drug Enforcement Agency registration to prescribe schedule II controlled substances would be required to certify that they were trained to safely prescribe and choose the appropriate patients for the drugs. Currently, a physician can obtain DEA registration without a training requirement. Giving the DEA such authority would require an act of Congress, according to one of the industry working group representatives.

Voluntary programs could be developed, possibly with medical specialty societies, while legislative efforts are underway, the working group noted.

Requiring such training raises the concern that some physicians would opt out of training—thus reducing access to the drugs for patients who need them, said Dr. John Jenkins, director of the Office of New Drugs, in the FDA's Center for Drug Evaluation and Research.

The REMS program's goals are to ensure that the drugs' benefits exceed their risks, while providing access for patients who need them, Dr. Jenkins noted during a press briefing after the meeting.

The drugs to be included in the REMS are brand-name and generic products that contain fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Among the problems associated with those products include their use in patients who are nonopioid tolerant or otherwise inappropriately selected, as well as misuse and abuse of the drugs.

Dr. Jenkins cited the example of pain treatment with methadone—which, when taken too frequently, can result rapidly in an overdose.

Short-acting opioid products were not discussed, but meeting participants expressed concern that an effective REMS for long-acting products could shift misuse and abuse to shorter-acting agents.

The working group also proposed these ideas:

▸ A patient-prescriber agreement. This would serve as a tool to facilitate discussion between the physician and patient.

▸ A medication information sheet.

▸ Metrics to assess the impact of the REMS. There should be a measure to determine whether the REMS impedes patients' access to appropriate medication, the working group noted.

The working group made no definitive conclusions at the meeting and has not developed a final plan for the REMS.

Dr. Jenkins said he couldn't predict when the REMS would be finalized. But an FDA advisory panel will meet in the spring to discuss the elements of the proposed REMS, to solicit advice from experts, and to hear public comment, he added. Until a final REMS is approved, Dr. Jenkins said, the FDA will require an interim REMS for any product in this drug class.

My Take

Pain Treatment Could Be Restricted

Requiring physicians to undergo training in order to prescribe opioids would be a major impediment to the care of patients. Most of the physicians I have spoken to say they would not take such training and would instead simply stop prescribing the related drugs. The problem is that most of us have a few patients requiring long-term narcotics, but just a few, and most narcotic use in rheumatology is short term or limited long-term use (e.g., 20 tablets for 3-6 months).

The patient-prescriber agreement is important but is really only needed for patients using continuous long-term narcotics. The medication information sheet is a good idea, but what is the role of the pharmacist? In many states, the pharmacist has access to electronic records of narcotic prescriptions. Shouldn't they have the responsibility of notifying physicians of misuse?

It seems to me that the imposition of training and compulsory use of forms would not reduce the risk of addiction or improve detection of abuse, but it would add another layer of rules and make it more difficult to practice medicine and provide appropriate patient care.

ROY ALTMAN, M.D., is professor of rheumatology and immunology at the University of California Los Angeles. Dr. Altman reported having financial relationships with numerous pharmaceutical companies.

Vitals

COLLEGE PARK, MD. — Special training in safe prescription of long-acting opioid drugs, as well as the use of patient-prescriber agreements, could be required to earn federal approval to prescribe such products, under proposals discussed by an industry working group.

At a public meeting held by the Food and Drug Administration, the working group presented those and other options as part of an initiative to develop a class-wide risk evaluation and mitigation strategy (REMS) for long-acting opioid drugs.

In February 2009, the FDA informed manufacturers of long-acting opioid products that they would have to develop a single REMS for the drug class. The FDA wants to reduce abuse, misuse, overdose, and addiction associated with the use of the products, and to ensure that their benefits outweigh their risks.

Under one element of the plan under consideration, clinicians seeking Drug Enforcement Agency registration to prescribe schedule II controlled substances would be required to certify that they were trained to safely prescribe and choose the appropriate patients for the drugs. Currently, a physician can obtain DEA registration without a training requirement. Giving the DEA such authority would require an act of Congress, according to one of the industry working group representatives.

Voluntary programs could be developed, possibly with medical specialty societies, while legislative efforts are underway, the working group noted.

Requiring such training raises the concern that some physicians would opt out of training—thus reducing access to the drugs for patients who need them, said Dr. John Jenkins, director of the Office of New Drugs, in the FDA's Center for Drug Evaluation and Research.

The REMS program's goals are to ensure that the drugs' benefits exceed their risks, while providing access for patients who need them, Dr. Jenkins noted during a press briefing after the meeting.

The drugs to be included in the REMS are brand-name and generic products that contain fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Among the problems associated with those products include their use in patients who are nonopioid tolerant or otherwise inappropriately selected, as well as misuse and abuse of the drugs.

Dr. Jenkins cited the example of pain treatment with methadone—which, when taken too frequently, can result rapidly in an overdose.

Short-acting opioid products were not discussed, but meeting participants expressed concern that an effective REMS for long-acting products could shift misuse and abuse to shorter-acting agents.

The working group also proposed these ideas:

▸ A patient-prescriber agreement. This would serve as a tool to facilitate discussion between the physician and patient.

▸ A medication information sheet.

▸ Metrics to assess the impact of the REMS. There should be a measure to determine whether the REMS impedes patients' access to appropriate medication, the working group noted.

The working group made no definitive conclusions at the meeting and has not developed a final plan for the REMS.

Dr. Jenkins said he couldn't predict when the REMS would be finalized. But an FDA advisory panel will meet in the spring to discuss the elements of the proposed REMS, to solicit advice from experts, and to hear public comment, he added. Until a final REMS is approved, Dr. Jenkins said, the FDA will require an interim REMS for any product in this drug class.

My Take

Pain Treatment Could Be Restricted

Requiring physicians to undergo training in order to prescribe opioids would be a major impediment to the care of patients. Most of the physicians I have spoken to say they would not take such training and would instead simply stop prescribing the related drugs. The problem is that most of us have a few patients requiring long-term narcotics, but just a few, and most narcotic use in rheumatology is short term or limited long-term use (e.g., 20 tablets for 3-6 months).

The patient-prescriber agreement is important but is really only needed for patients using continuous long-term narcotics. The medication information sheet is a good idea, but what is the role of the pharmacist? In many states, the pharmacist has access to electronic records of narcotic prescriptions. Shouldn't they have the responsibility of notifying physicians of misuse?

It seems to me that the imposition of training and compulsory use of forms would not reduce the risk of addiction or improve detection of abuse, but it would add another layer of rules and make it more difficult to practice medicine and provide appropriate patient care.

ROY ALTMAN, M.D., is professor of rheumatology and immunology at the University of California Los Angeles. Dr. Altman reported having financial relationships with numerous pharmaceutical companies.

Vitals

The potential health effects of exposure to bisphenol A, the chemical compound used in baby bottles and many different food and beverage packages, will be studied in short- and long-term trials in animals and humans, William Corr, deputy secretary of the Department of Health and Human Services, announced during a briefing.

More than $30 million will be provided by the National Institute of Environmental Health Sciences for studies to be conducted by the Food and Drug Administration, the National Institutes of Health, and other institutions. Results are expected in 18-24 months, he said.

In the meantime, HHS has issued recommendations for consumers on simple steps they can take now to reduce infants' exposure to BPA, including discarding scratched baby bottles and infant “sippie” cups and being careful about how breast milk or formula is heated, he said. The recommendations, with information on what is currently understood about the effects of BPA on health, are posted on the HHS Web site (www.hhs.gov/safety/bpa

BPA is a component of the epoxy resin that lines many food containers, as well as plastic used in a range of products that includes baby bottles and water bottles. Small amounts of BPA have been detected in canned liquid infant formula, but powdered formula generally does not have detectable levels, according to HHS.

During the briefing, Linda Birnbaum, Ph.D., director of the National Institute of Environmental Health Sciences and director of the National Toxicology Program (NTP), said that a “growing body of evidence” indicates that BPA exposure may be harmful to humans, but more data are needed on the potential health effects, which might involve behavior, obesity, reproductive disorders, diabetes, cardiovascular disease, asthma, and cancer.

FDA commissioner Dr. Margaret Hamburg said at the briefing that the FDA's assessment of the potential risks of BPA exposure is now in line with the NTP's assessment that there is a basis for “some concern.” In an August 2008 draft assessment of the health risks of BPA, the FDA said that, based on a review of toxicology research and other information, exposure to BPA-containing materials is safe. However, the NTP followed with a report that concluded there was a basis for “some concern” about the potential health effects of BPA. The FDA's change in position was a result of the agency's evaluation of data that became available since the NTP report was released, Dr. Hamburg said.

The recommendations for parents include the advice to follow guidelines for feeding infants, which includes breastfeeding for at least 12 months. If breastfeeding is not an option, iron-fortified formula is the safest and most nutritious alternative, and although trace amounts of BPA have been detected in canned formula, good nutrition “outweighs any potential risks of BPA,” Mr. Corr said.

The recommendations also advise letting boiled water cool to a lukewarm temperature before mixing it with powdered formula, avoiding heating baby bottles in a microwave, allowing bottles to cool to room temperature before adding infant formula, and avoiding putting boiling or very hot water, formula, or any other liquids in bottles that contain BPA.

According to the HHS information sheet, the six major manufacturers of baby bottles and infant feeding cups—which represent over 90% of the U.S. market—have not manufactured these products with BPA for the U.S. market since January 2009.

More information is available at www.fda.gov/downloads/NewsEvents/PublicHealthFocus/UCM197778.pdf

The potential health effects of exposure to bisphenol A, the chemical compound used in baby bottles and many different food and beverage packages, will be studied in short- and long-term trials in animals and humans, William Corr, deputy secretary of the Department of Health and Human Services, announced during a briefing.

More than $30 million will be provided by the National Institute of Environmental Health Sciences for studies to be conducted by the Food and Drug Administration, the National Institutes of Health, and other institutions. Results are expected in 18-24 months, he said.

In the meantime, HHS has issued recommendations for consumers on simple steps they can take now to reduce infants' exposure to BPA, including discarding scratched baby bottles and infant “sippie” cups and being careful about how breast milk or formula is heated, he said. The recommendations, with information on what is currently understood about the effects of BPA on health, are posted on the HHS Web site (www.hhs.gov/safety/bpa

BPA is a component of the epoxy resin that lines many food containers, as well as plastic used in a range of products that includes baby bottles and water bottles. Small amounts of BPA have been detected in canned liquid infant formula, but powdered formula generally does not have detectable levels, according to HHS.

During the briefing, Linda Birnbaum, Ph.D., director of the National Institute of Environmental Health Sciences and director of the National Toxicology Program (NTP), said that a “growing body of evidence” indicates that BPA exposure may be harmful to humans, but more data are needed on the potential health effects, which might involve behavior, obesity, reproductive disorders, diabetes, cardiovascular disease, asthma, and cancer.

FDA commissioner Dr. Margaret Hamburg said at the briefing that the FDA's assessment of the potential risks of BPA exposure is now in line with the NTP's assessment that there is a basis for “some concern.” In an August 2008 draft assessment of the health risks of BPA, the FDA said that, based on a review of toxicology research and other information, exposure to BPA-containing materials is safe. However, the NTP followed with a report that concluded there was a basis for “some concern” about the potential health effects of BPA. The FDA's change in position was a result of the agency's evaluation of data that became available since the NTP report was released, Dr. Hamburg said.

The recommendations for parents include the advice to follow guidelines for feeding infants, which includes breastfeeding for at least 12 months. If breastfeeding is not an option, iron-fortified formula is the safest and most nutritious alternative, and although trace amounts of BPA have been detected in canned formula, good nutrition “outweighs any potential risks of BPA,” Mr. Corr said.

The recommendations also advise letting boiled water cool to a lukewarm temperature before mixing it with powdered formula, avoiding heating baby bottles in a microwave, allowing bottles to cool to room temperature before adding infant formula, and avoiding putting boiling or very hot water, formula, or any other liquids in bottles that contain BPA.

According to the HHS information sheet, the six major manufacturers of baby bottles and infant feeding cups—which represent over 90% of the U.S. market—have not manufactured these products with BPA for the U.S. market since January 2009.

More information is available at www.fda.gov/downloads/NewsEvents/PublicHealthFocus/UCM197778.pdf

The potential health effects of exposure to bisphenol A, the chemical compound used in baby bottles and many different food and beverage packages, will be studied in short- and long-term trials in animals and humans, William Corr, deputy secretary of the Department of Health and Human Services, announced during a briefing.

More than $30 million will be provided by the National Institute of Environmental Health Sciences for studies to be conducted by the Food and Drug Administration, the National Institutes of Health, and other institutions. Results are expected in 18-24 months, he said.

In the meantime, HHS has issued recommendations for consumers on simple steps they can take now to reduce infants' exposure to BPA, including discarding scratched baby bottles and infant “sippie” cups and being careful about how breast milk or formula is heated, he said. The recommendations, with information on what is currently understood about the effects of BPA on health, are posted on the HHS Web site (www.hhs.gov/safety/bpa

BPA is a component of the epoxy resin that lines many food containers, as well as plastic used in a range of products that includes baby bottles and water bottles. Small amounts of BPA have been detected in canned liquid infant formula, but powdered formula generally does not have detectable levels, according to HHS.

During the briefing, Linda Birnbaum, Ph.D., director of the National Institute of Environmental Health Sciences and director of the National Toxicology Program (NTP), said that a “growing body of evidence” indicates that BPA exposure may be harmful to humans, but more data are needed on the potential health effects, which might involve behavior, obesity, reproductive disorders, diabetes, cardiovascular disease, asthma, and cancer.

FDA commissioner Dr. Margaret Hamburg said at the briefing that the FDA's assessment of the potential risks of BPA exposure is now in line with the NTP's assessment that there is a basis for “some concern.” In an August 2008 draft assessment of the health risks of BPA, the FDA said that, based on a review of toxicology research and other information, exposure to BPA-containing materials is safe. However, the NTP followed with a report that concluded there was a basis for “some concern” about the potential health effects of BPA. The FDA's change in position was a result of the agency's evaluation of data that became available since the NTP report was released, Dr. Hamburg said.

The recommendations for parents include the advice to follow guidelines for feeding infants, which includes breastfeeding for at least 12 months. If breastfeeding is not an option, iron-fortified formula is the safest and most nutritious alternative, and although trace amounts of BPA have been detected in canned formula, good nutrition “outweighs any potential risks of BPA,” Mr. Corr said.

The recommendations also advise letting boiled water cool to a lukewarm temperature before mixing it with powdered formula, avoiding heating baby bottles in a microwave, allowing bottles to cool to room temperature before adding infant formula, and avoiding putting boiling or very hot water, formula, or any other liquids in bottles that contain BPA.

According to the HHS information sheet, the six major manufacturers of baby bottles and infant feeding cups—which represent over 90% of the U.S. market—have not manufactured these products with BPA for the U.S. market since January 2009.

More information is available at www.fda.gov/downloads/NewsEvents/PublicHealthFocus/UCM197778.pdf

A product called Nzu that is used to treat morning sickness contains high levels of arsenic and lead and should not be used by pregnant or breastfeeding women, the Food and Drug Administration warned in a statement posted on the agency's MedWatch site.

Nzu, a traditional remedy for morning sickness, is sold at African specialty stores and is also called Calabash clay, Calabar stone, Mabele, Argile, and La Craie. “It generally resembles balls of clay or mud and is usually sold in small plastic bags with a handwritten label identifying it as 'Nzu' or 'Salted Nzu,'” the statement said.

Lead exposure can harm the brain and nervous system of developing children. Long-term exposure to arsenic, a carcinogen, has been linked with bladder, lung, and skin cancer, according to the agency.

The high levels of arsenic and lead were detected in laboratory tests performed by the Texas Department of State Health Services (DSHS), which issued a warning about the potential health risks associated with these products. DSHS inspectors tested products at two African specialty stores, one in the Dallas area and one in Houston. A DSHS statement announcing these findings said that the Nzu products may be covered in a brown or white “dust.”

“This report supports the evidence that so-called natural remedies are not always safe or effective,” said Gerald G. Briggs, B.Pharm., a clinical professor of pharmacy at the University of California, San Francisco. Instead, he recommends doxylamine and vitamin B₆, which are available over the counter.

A link to the notice is available at www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm196045.htm

A product called Nzu that is used to treat morning sickness contains high levels of arsenic and lead and should not be used by pregnant or breastfeeding women, the Food and Drug Administration warned in a statement posted on the agency's MedWatch site.

Nzu, a traditional remedy for morning sickness, is sold at African specialty stores and is also called Calabash clay, Calabar stone, Mabele, Argile, and La Craie. “It generally resembles balls of clay or mud and is usually sold in small plastic bags with a handwritten label identifying it as 'Nzu' or 'Salted Nzu,'” the statement said.

Lead exposure can harm the brain and nervous system of developing children. Long-term exposure to arsenic, a carcinogen, has been linked with bladder, lung, and skin cancer, according to the agency.

The high levels of arsenic and lead were detected in laboratory tests performed by the Texas Department of State Health Services (DSHS), which issued a warning about the potential health risks associated with these products. DSHS inspectors tested products at two African specialty stores, one in the Dallas area and one in Houston. A DSHS statement announcing these findings said that the Nzu products may be covered in a brown or white “dust.”

“This report supports the evidence that so-called natural remedies are not always safe or effective,” said Gerald G. Briggs, B.Pharm., a clinical professor of pharmacy at the University of California, San Francisco. Instead, he recommends doxylamine and vitamin B₆, which are available over the counter.

A link to the notice is available at www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm196045.htm

A product called Nzu that is used to treat morning sickness contains high levels of arsenic and lead and should not be used by pregnant or breastfeeding women, the Food and Drug Administration warned in a statement posted on the agency's MedWatch site.

Nzu, a traditional remedy for morning sickness, is sold at African specialty stores and is also called Calabash clay, Calabar stone, Mabele, Argile, and La Craie. “It generally resembles balls of clay or mud and is usually sold in small plastic bags with a handwritten label identifying it as 'Nzu' or 'Salted Nzu,'” the statement said.

Lead exposure can harm the brain and nervous system of developing children. Long-term exposure to arsenic, a carcinogen, has been linked with bladder, lung, and skin cancer, according to the agency.

The high levels of arsenic and lead were detected in laboratory tests performed by the Texas Department of State Health Services (DSHS), which issued a warning about the potential health risks associated with these products. DSHS inspectors tested products at two African specialty stores, one in the Dallas area and one in Houston. A DSHS statement announcing these findings said that the Nzu products may be covered in a brown or white “dust.”

“This report supports the evidence that so-called natural remedies are not always safe or effective,” said Gerald G. Briggs, B.Pharm., a clinical professor of pharmacy at the University of California, San Francisco. Instead, he recommends doxylamine and vitamin B₆, which are available over the counter.

A link to the notice is available at www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm196045.htm

Major Finding: Adults undergoing screening colonoscopy within 10 years of a previous colonoscopy had a significantly lower risk of having a left-sided advanced neoplasm detected, but their risk of right-sided neoplasms was not reduced.

Data Source: A population-based study of 3,287 adults aged 55 and older presenting for a screening colonoscopy at 33 German gastroenterology practices between May 1, 2005, and Dec. 31, 2007.

Disclosures: Study partly supported by the Central Research Institute of Ambulatory Health Care in Germany (Berlin).

The risk of left-sided advanced colorectal neoplasms was reduced by 67% within 10 years of having a screening colonoscopy, but there was no reduction in risk of right-sided neoplasms in a German community-based study of more than 3,000 people.

“Although a strong protective effect of colonoscopy from colorectal neoplasms has been established through previous studies, our results add to the evidence that this effect is much stronger in, if not confined to, the left colon and rectum, at least in the community setting,” concluded Dr. Hermann Brenner and his associates of the division of clinical epidemiology and aging research at the German Cancer Research Center, Heidelberg.

The lack of an effect in the right colon could “be overcome to some extent by enhanced training of endoscopists, by enhanced measures of quality assurance, and by development of technology that enhances inspection of the right colon,” they added (J. Natl. Cancer Inst. 2009;102:1-7).

The study included 3,287 people older than 55 years undergoing a screening colonoscopy at 33 gastroenterology practices in Saarland (Germany) between May 1, 2005, and Dec. 31, 2007. The researchers compared the prevalence of colorectal cancer and advanced adenomas (combined as “advanced colorectal neoplasm”) among those who reported having had a colonoscopy within the previous decade to the prevalence among those who said they had not had a colonoscopy previously.

An advanced colorectal neoplasm was found in 308 of the 2,701 participants (11.4%) who had not had a colonoscopy previously, compared with 36 of the 586 participants (6.1%) who had had a colonoscopy 1-10 years earlier. One case of colorectal cancer occurred in those who had undergone colonoscopy, and 41 cases in those who had not.

After adjusting for age, sex, and family history of colorectal cancer, the prevalence ratio of colorectal cancer was 0.52 overall. “However, in site-specific analyses, previous colonoscopy was strongly and inversely associated with prevalence of advanced neoplasia in the left-sided colon and rectum but not with prevalence of advanced neoplasia in the right-sided colon,” they reported.

The adjusted prevalence ratios were as follows: 0.99 for the cecum and ascending colon, 1.21 for the hepatic flexure and transverse colon, 0.36 for the splenic flexure and descending colon, 0.29 for the sigmoid colon, and 0.07 for the rectum.

Possible reasons for the lack of an effect of previous colonoscopy on the prevalence of right-sided neoplasms include incomplete colonoscopies or worse bowel preparation in the right colon, which could result in some missed right-sided adenomas, the authors suggested. There also could be a higher proportion of adenomas in the right colon that are sessile and flat, compared with the proportion in the left colon and rectum, they added, noting that these adenomas are easier to miss and more difficult to remove.

The authors pointed out that their results were similar to the odds ratio of deaths in a community-based study in Canada that used administrative claims data (Ann. Intern. Med. 2009;150:1-8). In this study, having a colonoscopy within 6 months of a diagnosis was associated with about a 40% lower risk of colorectal cancer mortality. This benefit also was “restricted essentially to left-sided colorectal cancers.”

In an accompanying editorial, the lead author of that study, Dr. Nancy Baxter of St. Michael's Hospital, Toronto, referred to some limitations of the German study, but pointed out that the results were “remarkably consistent with a number of recently published studies, all of which demonstrate the overall effectiveness of colonoscopy for reducing colorectal cancer incidence and mortality, but with a marked variance in effectiveness for proximal and distal cancers” (J. Natl. Cancer Inst. 2009;102:70-1).

My Take

Results Are Cause for Concern

We must be concerned about these results because studies in several settings have reported that protection from colonoscopy in the right colon is not as good as it is in the left colon, and we don't understand the reasons.

A study of the California MediCal population, the only one done in the United States, showed the same trend, but differed from the German and Canadian studies in that there was still some protection in the right colon (about 60% in men; only about 20% in women).

There are two categories of explanations for poor right colon protection from colonoscopy. One is that differing biologic factors between right and left colon cancers prevent us from achieving effective cancer prevention. The second category of explanations involves technical issues in colonoscopy performance that may affect right colon detection, including failed cecal intubation, poor preparation (which affects the right colon preferentially), and flat lesions and serrated polyps, both of which are more common in the right colon and easier to miss at colonoscopy, compared with traditional adenomas.

We can probably correct a significant portion of this problem by improving colonoscopy performance. First, everyone should use split-dose bowel preparations. There are now 10 randomized, controlled trials showing that splitting the prep—giving half of it on the day of the procedure—improves the preparation in the ascending colon. Second, we need all colonoscopists to photodocument the cecum. Finally, increased awareness and perhaps special training are needed to improve detection of flat and serrated polyps.

We have a lot of information that adenoma detection is operator-dependent and varies dramatically between endoscopists. Colonoscopists should now be measuring their adenoma detection rates. We also need to figure out what serrated lesion detection rates should be over the next few years and institute quality indicators for this end point. We must reduce the operator dependency of colonoscopy. It's a flaw in the strategy when a procedure that is so important for prevention of a common cancer is operator dependent.

DOUGLAS K. REX, M.D., is distinguished professor of medicine at Indiana University, Indianapolis, and director of endoscopy at Indiana University Hospital, Indianapolis.

Vitals

Major Finding: Adults undergoing screening colonoscopy within 10 years of a previous colonoscopy had a significantly lower risk of having a left-sided advanced neoplasm detected, but their risk of right-sided neoplasms was not reduced.

Data Source: A population-based study of 3,287 adults aged 55 and older presenting for a screening colonoscopy at 33 German gastroenterology practices between May 1, 2005, and Dec. 31, 2007.

Disclosures: Study partly supported by the Central Research Institute of Ambulatory Health Care in Germany (Berlin).

The risk of left-sided advanced colorectal neoplasms was reduced by 67% within 10 years of having a screening colonoscopy, but there was no reduction in risk of right-sided neoplasms in a German community-based study of more than 3,000 people.

“Although a strong protective effect of colonoscopy from colorectal neoplasms has been established through previous studies, our results add to the evidence that this effect is much stronger in, if not confined to, the left colon and rectum, at least in the community setting,” concluded Dr. Hermann Brenner and his associates of the division of clinical epidemiology and aging research at the German Cancer Research Center, Heidelberg.

The lack of an effect in the right colon could “be overcome to some extent by enhanced training of endoscopists, by enhanced measures of quality assurance, and by development of technology that enhances inspection of the right colon,” they added (J. Natl. Cancer Inst. 2009;102:1-7).

The study included 3,287 people older than 55 years undergoing a screening colonoscopy at 33 gastroenterology practices in Saarland (Germany) between May 1, 2005, and Dec. 31, 2007. The researchers compared the prevalence of colorectal cancer and advanced adenomas (combined as “advanced colorectal neoplasm”) among those who reported having had a colonoscopy within the previous decade to the prevalence among those who said they had not had a colonoscopy previously.

An advanced colorectal neoplasm was found in 308 of the 2,701 participants (11.4%) who had not had a colonoscopy previously, compared with 36 of the 586 participants (6.1%) who had had a colonoscopy 1-10 years earlier. One case of colorectal cancer occurred in those who had undergone colonoscopy, and 41 cases in those who had not.

After adjusting for age, sex, and family history of colorectal cancer, the prevalence ratio of colorectal cancer was 0.52 overall. “However, in site-specific analyses, previous colonoscopy was strongly and inversely associated with prevalence of advanced neoplasia in the left-sided colon and rectum but not with prevalence of advanced neoplasia in the right-sided colon,” they reported.

The adjusted prevalence ratios were as follows: 0.99 for the cecum and ascending colon, 1.21 for the hepatic flexure and transverse colon, 0.36 for the splenic flexure and descending colon, 0.29 for the sigmoid colon, and 0.07 for the rectum.

Possible reasons for the lack of an effect of previous colonoscopy on the prevalence of right-sided neoplasms include incomplete colonoscopies or worse bowel preparation in the right colon, which could result in some missed right-sided adenomas, the authors suggested. There also could be a higher proportion of adenomas in the right colon that are sessile and flat, compared with the proportion in the left colon and rectum, they added, noting that these adenomas are easier to miss and more difficult to remove.

The authors pointed out that their results were similar to the odds ratio of deaths in a community-based study in Canada that used administrative claims data (Ann. Intern. Med. 2009;150:1-8). In this study, having a colonoscopy within 6 months of a diagnosis was associated with about a 40% lower risk of colorectal cancer mortality. This benefit also was “restricted essentially to left-sided colorectal cancers.”

In an accompanying editorial, the lead author of that study, Dr. Nancy Baxter of St. Michael's Hospital, Toronto, referred to some limitations of the German study, but pointed out that the results were “remarkably consistent with a number of recently published studies, all of which demonstrate the overall effectiveness of colonoscopy for reducing colorectal cancer incidence and mortality, but with a marked variance in effectiveness for proximal and distal cancers” (J. Natl. Cancer Inst. 2009;102:70-1).

My Take

Results Are Cause for Concern

We must be concerned about these results because studies in several settings have reported that protection from colonoscopy in the right colon is not as good as it is in the left colon, and we don't understand the reasons.

A study of the California MediCal population, the only one done in the United States, showed the same trend, but differed from the German and Canadian studies in that there was still some protection in the right colon (about 60% in men; only about 20% in women).

There are two categories of explanations for poor right colon protection from colonoscopy. One is that differing biologic factors between right and left colon cancers prevent us from achieving effective cancer prevention. The second category of explanations involves technical issues in colonoscopy performance that may affect right colon detection, including failed cecal intubation, poor preparation (which affects the right colon preferentially), and flat lesions and serrated polyps, both of which are more common in the right colon and easier to miss at colonoscopy, compared with traditional adenomas.

We can probably correct a significant portion of this problem by improving colonoscopy performance. First, everyone should use split-dose bowel preparations. There are now 10 randomized, controlled trials showing that splitting the prep—giving half of it on the day of the procedure—improves the preparation in the ascending colon. Second, we need all colonoscopists to photodocument the cecum. Finally, increased awareness and perhaps special training are needed to improve detection of flat and serrated polyps.

We have a lot of information that adenoma detection is operator-dependent and varies dramatically between endoscopists. Colonoscopists should now be measuring their adenoma detection rates. We also need to figure out what serrated lesion detection rates should be over the next few years and institute quality indicators for this end point. We must reduce the operator dependency of colonoscopy. It's a flaw in the strategy when a procedure that is so important for prevention of a common cancer is operator dependent.

DOUGLAS K. REX, M.D., is distinguished professor of medicine at Indiana University, Indianapolis, and director of endoscopy at Indiana University Hospital, Indianapolis.

Vitals

Major Finding: Adults undergoing screening colonoscopy within 10 years of a previous colonoscopy had a significantly lower risk of having a left-sided advanced neoplasm detected, but their risk of right-sided neoplasms was not reduced.

Data Source: A population-based study of 3,287 adults aged 55 and older presenting for a screening colonoscopy at 33 German gastroenterology practices between May 1, 2005, and Dec. 31, 2007.

Disclosures: Study partly supported by the Central Research Institute of Ambulatory Health Care in Germany (Berlin).

The risk of left-sided advanced colorectal neoplasms was reduced by 67% within 10 years of having a screening colonoscopy, but there was no reduction in risk of right-sided neoplasms in a German community-based study of more than 3,000 people.

“Although a strong protective effect of colonoscopy from colorectal neoplasms has been established through previous studies, our results add to the evidence that this effect is much stronger in, if not confined to, the left colon and rectum, at least in the community setting,” concluded Dr. Hermann Brenner and his associates of the division of clinical epidemiology and aging research at the German Cancer Research Center, Heidelberg.

The lack of an effect in the right colon could “be overcome to some extent by enhanced training of endoscopists, by enhanced measures of quality assurance, and by development of technology that enhances inspection of the right colon,” they added (J. Natl. Cancer Inst. 2009;102:1-7).

The study included 3,287 people older than 55 years undergoing a screening colonoscopy at 33 gastroenterology practices in Saarland (Germany) between May 1, 2005, and Dec. 31, 2007. The researchers compared the prevalence of colorectal cancer and advanced adenomas (combined as “advanced colorectal neoplasm”) among those who reported having had a colonoscopy within the previous decade to the prevalence among those who said they had not had a colonoscopy previously.

An advanced colorectal neoplasm was found in 308 of the 2,701 participants (11.4%) who had not had a colonoscopy previously, compared with 36 of the 586 participants (6.1%) who had had a colonoscopy 1-10 years earlier. One case of colorectal cancer occurred in those who had undergone colonoscopy, and 41 cases in those who had not.

After adjusting for age, sex, and family history of colorectal cancer, the prevalence ratio of colorectal cancer was 0.52 overall. “However, in site-specific analyses, previous colonoscopy was strongly and inversely associated with prevalence of advanced neoplasia in the left-sided colon and rectum but not with prevalence of advanced neoplasia in the right-sided colon,” they reported.

The adjusted prevalence ratios were as follows: 0.99 for the cecum and ascending colon, 1.21 for the hepatic flexure and transverse colon, 0.36 for the splenic flexure and descending colon, 0.29 for the sigmoid colon, and 0.07 for the rectum.

Possible reasons for the lack of an effect of previous colonoscopy on the prevalence of right-sided neoplasms include incomplete colonoscopies or worse bowel preparation in the right colon, which could result in some missed right-sided adenomas, the authors suggested. There also could be a higher proportion of adenomas in the right colon that are sessile and flat, compared with the proportion in the left colon and rectum, they added, noting that these adenomas are easier to miss and more difficult to remove.

The authors pointed out that their results were similar to the odds ratio of deaths in a community-based study in Canada that used administrative claims data (Ann. Intern. Med. 2009;150:1-8). In this study, having a colonoscopy within 6 months of a diagnosis was associated with about a 40% lower risk of colorectal cancer mortality. This benefit also was “restricted essentially to left-sided colorectal cancers.”

In an accompanying editorial, the lead author of that study, Dr. Nancy Baxter of St. Michael's Hospital, Toronto, referred to some limitations of the German study, but pointed out that the results were “remarkably consistent with a number of recently published studies, all of which demonstrate the overall effectiveness of colonoscopy for reducing colorectal cancer incidence and mortality, but with a marked variance in effectiveness for proximal and distal cancers” (J. Natl. Cancer Inst. 2009;102:70-1).

My Take

Results Are Cause for Concern

We must be concerned about these results because studies in several settings have reported that protection from colonoscopy in the right colon is not as good as it is in the left colon, and we don't understand the reasons.

A study of the California MediCal population, the only one done in the United States, showed the same trend, but differed from the German and Canadian studies in that there was still some protection in the right colon (about 60% in men; only about 20% in women).

There are two categories of explanations for poor right colon protection from colonoscopy. One is that differing biologic factors between right and left colon cancers prevent us from achieving effective cancer prevention. The second category of explanations involves technical issues in colonoscopy performance that may affect right colon detection, including failed cecal intubation, poor preparation (which affects the right colon preferentially), and flat lesions and serrated polyps, both of which are more common in the right colon and easier to miss at colonoscopy, compared with traditional adenomas.

We can probably correct a significant portion of this problem by improving colonoscopy performance. First, everyone should use split-dose bowel preparations. There are now 10 randomized, controlled trials showing that splitting the prep—giving half of it on the day of the procedure—improves the preparation in the ascending colon. Second, we need all colonoscopists to photodocument the cecum. Finally, increased awareness and perhaps special training are needed to improve detection of flat and serrated polyps.

We have a lot of information that adenoma detection is operator-dependent and varies dramatically between endoscopists. Colonoscopists should now be measuring their adenoma detection rates. We also need to figure out what serrated lesion detection rates should be over the next few years and institute quality indicators for this end point. We must reduce the operator dependency of colonoscopy. It's a flaw in the strategy when a procedure that is so important for prevention of a common cancer is operator dependent.

DOUGLAS K. REX, M.D., is distinguished professor of medicine at Indiana University, Indianapolis, and director of endoscopy at Indiana University Hospital, Indianapolis.

Vitals

A review of data from three studies indicates that simvastatin, ezetimibe, or the combination of the two are not likely to be increase the risk of cancer or death from cancer, but that the association cannot be “definitively ruled out,” the Food and Drug Administration announced.

The FDA announcement is a follow-up to an announcement made by the agency in August 2008 about a safety review of these products, based on the preliminary results of the Simvasatatin and Ezetimibe in Aortic Stenosis (SEAS) trial of 1,873 patents with aortic stenosis, which found a higher rate of cancer (11.1%) among those on Vytorin 10/40 (10 mg of ezetimibe and 40 mg of simvastatin), compared with those on placebo (7.5%). The number of cancer-related deaths was also higher among those on Vytorin in this study. Vytorin is a combination of simvastatin (Zocor) and ezetimibe (Zetia).

The FDA has finished a review of data from SEAS, which is completed, and interim data from two large ongoing studies with lower doses of Vytorin, the SHARP (Study of Heart and Renal Protection) and IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

“Based on the currently available information, FDA believes it is unlikely that Vytorin or Zetia increase the risk of cancer or cancer-related death, but at this time an association cannot be definitively ruled out,” the statement said. “FDA is not advising healthcare professionals or consumers to stop using these medications, but to continue to evaluate the clinical benefits and potential risks of Vytorin or Zetia compared to other FDA-approved cholesterol lowering medications.”

The SHARP study compares Vytorin (10/20 mg) to placebo, to determine whether reducing cholesterol with the combination product can prevent heart disease and strokes in patients with kidney disease.

IMPROVE-IT is comparing the clinical benefit (the reduction in the risk of the composite end point of cardiovascular death, major coronary events, and stroke) of Vytorin (10/40 mg) to 40 mg of simvastatin, in high-risk subjects with stabilized high-risk acute coronary syndrome.

An interim analysis of a total of 20,617 patients from these two studies found no increased risk of cancer associated with Vytorin. There were 97 cancer-related deaths, however, compared with 72 deaths among those in the control groups, but the difference was not statistically significant.

The cancer risk associated with Vytorin will be evaluated further when these studies are completed in 2010 (SHARP) and 2012 (IMPROVE-IT), according to the FDA.

Other factors that the agency considered in its review included animal studies that did not find an association between ezetimibe and an increased incidence of cancer.

In addition, there was not a consistent increase in the risk of cancer over time in the SEAS study, which would be expected if the drug caused cancer or promoted the growth of preexisting cancers, and the increase in cancer and cancer deaths in the study was due to combining a variety of cancer types, according to the statement.

The notice can be found at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm194964.htmwww.fda.gov/medwatch

A review of data from three studies indicates that simvastatin, ezetimibe, or the combination of the two are not likely to be increase the risk of cancer or death from cancer, but that the association cannot be “definitively ruled out,” the Food and Drug Administration announced.

The FDA announcement is a follow-up to an announcement made by the agency in August 2008 about a safety review of these products, based on the preliminary results of the Simvasatatin and Ezetimibe in Aortic Stenosis (SEAS) trial of 1,873 patents with aortic stenosis, which found a higher rate of cancer (11.1%) among those on Vytorin 10/40 (10 mg of ezetimibe and 40 mg of simvastatin), compared with those on placebo (7.5%). The number of cancer-related deaths was also higher among those on Vytorin in this study. Vytorin is a combination of simvastatin (Zocor) and ezetimibe (Zetia).

The FDA has finished a review of data from SEAS, which is completed, and interim data from two large ongoing studies with lower doses of Vytorin, the SHARP (Study of Heart and Renal Protection) and IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

“Based on the currently available information, FDA believes it is unlikely that Vytorin or Zetia increase the risk of cancer or cancer-related death, but at this time an association cannot be definitively ruled out,” the statement said. “FDA is not advising healthcare professionals or consumers to stop using these medications, but to continue to evaluate the clinical benefits and potential risks of Vytorin or Zetia compared to other FDA-approved cholesterol lowering medications.”

The SHARP study compares Vytorin (10/20 mg) to placebo, to determine whether reducing cholesterol with the combination product can prevent heart disease and strokes in patients with kidney disease.

IMPROVE-IT is comparing the clinical benefit (the reduction in the risk of the composite end point of cardiovascular death, major coronary events, and stroke) of Vytorin (10/40 mg) to 40 mg of simvastatin, in high-risk subjects with stabilized high-risk acute coronary syndrome.

An interim analysis of a total of 20,617 patients from these two studies found no increased risk of cancer associated with Vytorin. There were 97 cancer-related deaths, however, compared with 72 deaths among those in the control groups, but the difference was not statistically significant.

The cancer risk associated with Vytorin will be evaluated further when these studies are completed in 2010 (SHARP) and 2012 (IMPROVE-IT), according to the FDA.

Other factors that the agency considered in its review included animal studies that did not find an association between ezetimibe and an increased incidence of cancer.

In addition, there was not a consistent increase in the risk of cancer over time in the SEAS study, which would be expected if the drug caused cancer or promoted the growth of preexisting cancers, and the increase in cancer and cancer deaths in the study was due to combining a variety of cancer types, according to the statement.

The notice can be found at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm194964.htmwww.fda.gov/medwatch

A review of data from three studies indicates that simvastatin, ezetimibe, or the combination of the two are not likely to be increase the risk of cancer or death from cancer, but that the association cannot be “definitively ruled out,” the Food and Drug Administration announced.

The FDA announcement is a follow-up to an announcement made by the agency in August 2008 about a safety review of these products, based on the preliminary results of the Simvasatatin and Ezetimibe in Aortic Stenosis (SEAS) trial of 1,873 patents with aortic stenosis, which found a higher rate of cancer (11.1%) among those on Vytorin 10/40 (10 mg of ezetimibe and 40 mg of simvastatin), compared with those on placebo (7.5%). The number of cancer-related deaths was also higher among those on Vytorin in this study. Vytorin is a combination of simvastatin (Zocor) and ezetimibe (Zetia).

The FDA has finished a review of data from SEAS, which is completed, and interim data from two large ongoing studies with lower doses of Vytorin, the SHARP (Study of Heart and Renal Protection) and IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

“Based on the currently available information, FDA believes it is unlikely that Vytorin or Zetia increase the risk of cancer or cancer-related death, but at this time an association cannot be definitively ruled out,” the statement said. “FDA is not advising healthcare professionals or consumers to stop using these medications, but to continue to evaluate the clinical benefits and potential risks of Vytorin or Zetia compared to other FDA-approved cholesterol lowering medications.”

The SHARP study compares Vytorin (10/20 mg) to placebo, to determine whether reducing cholesterol with the combination product can prevent heart disease and strokes in patients with kidney disease.

IMPROVE-IT is comparing the clinical benefit (the reduction in the risk of the composite end point of cardiovascular death, major coronary events, and stroke) of Vytorin (10/40 mg) to 40 mg of simvastatin, in high-risk subjects with stabilized high-risk acute coronary syndrome.

An interim analysis of a total of 20,617 patients from these two studies found no increased risk of cancer associated with Vytorin. There were 97 cancer-related deaths, however, compared with 72 deaths among those in the control groups, but the difference was not statistically significant.

The cancer risk associated with Vytorin will be evaluated further when these studies are completed in 2010 (SHARP) and 2012 (IMPROVE-IT), according to the FDA.

Other factors that the agency considered in its review included animal studies that did not find an association between ezetimibe and an increased incidence of cancer.

In addition, there was not a consistent increase in the risk of cancer over time in the SEAS study, which would be expected if the drug caused cancer or promoted the growth of preexisting cancers, and the increase in cancer and cancer deaths in the study was due to combining a variety of cancer types, according to the statement.

The notice can be found at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm194964.htmwww.fda.gov/medwatch

The Food and Drug Administration is looking at recent data suggesting that the cardiovascular event rate among patients on the weight-loss drug sibutramine was higher than among those on placebo.

“The analysis of these data is ongoing and FDA is making no conclusions about the preliminary findings at this time,” according to a statement posted on the agency's MedWatch site. These findings, the statement adds, “highlight the importance of avoiding the use of sibutramine” in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or stroke, which is recommended in the current sibutramine label.

Sibutramine is an orally administered drug marketed as Meridia by Abbott Laboratories. Its therapeutic effects result from norepinephrine, serotonin, and dopamine reuptake inhibition, according to the label. It was approved in 1997 for the management of obesity in conjunction with a reduced-calorie diet, and is recommended only for obese patients with an initial body mass index at or above 30 kg/m

The FDA reported results from a study of about 10,000 overweight or obese patients aged 55 years or older who had a history of heart disease or type 2 diabetes and one additional cardiovascular risk factor. The preliminary results of the study's primary end point—MI, stroke, resuscitated cardiac arrest, or death—were reported in 11.4% of those on sibutramine, compared with 10% of those on placebo. The difference was “higher than expected, suggesting that sibutramine is associated with an increased cardiovascular risk in the study population,” the FDA noted.

Abbott started the study, Sibutramine Cardiovascular Morbidity/Mortality Outcomes in Overweight or Obese Subjects at Risk of a Cardiovascular Event (SCOUT), in 2002 at the request of the FDA's European counterpart, the European Medicines Agency (EMEA), as one of the conditions for keeping the drug on the market in Europe after serious cardiovascular events were reported in the early 2000s. The study's aim was to evaluate the safety and efficacy of sibutramine in overweight and obese people.

The FDA was apprised of the results in mid-November. On Dec. 3, Public Citizen's Health Research Group, a health advocacy organization, filed a citizen's petition calling on the FDA to withdraw the drug from the market immediately, because of the new data indicating that it increases the risk of MI, stroke, resuscitated cardiac arrest, or death.

In 2005, the FDA denied a previous petition by the group requesting that sibutramine be taken off the market because of concerns over its safety arising from preapproval clinical studies.

In an interview, Dr. Sidney Wolfe, director of the Washington-based Health Research Group, said that the preliminary results of the SCOUT trial are a concern. The group continues to support the withdrawal of sibutramine from the market and is analyzing sibutramine-related reports in the FDA's adverse event reporting system database, he said.

Despite the label's recommendation that patients with risk factors such as cardiovascular disease not be treated with sibutramine, the drug is still prescribed to patients who are obese and have some of these risk factors, he noted.

Report adverse events to the FDA's MedWatch program at 800-332-1088 or www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htmwww.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm191655.htm

The Food and Drug Administration is looking at recent data suggesting that the cardiovascular event rate among patients on the weight-loss drug sibutramine was higher than among those on placebo.

“The analysis of these data is ongoing and FDA is making no conclusions about the preliminary findings at this time,” according to a statement posted on the agency's MedWatch site. These findings, the statement adds, “highlight the importance of avoiding the use of sibutramine” in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or stroke, which is recommended in the current sibutramine label.

Sibutramine is an orally administered drug marketed as Meridia by Abbott Laboratories. Its therapeutic effects result from norepinephrine, serotonin, and dopamine reuptake inhibition, according to the label. It was approved in 1997 for the management of obesity in conjunction with a reduced-calorie diet, and is recommended only for obese patients with an initial body mass index at or above 30 kg/m

The FDA reported results from a study of about 10,000 overweight or obese patients aged 55 years or older who had a history of heart disease or type 2 diabetes and one additional cardiovascular risk factor. The preliminary results of the study's primary end point—MI, stroke, resuscitated cardiac arrest, or death—were reported in 11.4% of those on sibutramine, compared with 10% of those on placebo. The difference was “higher than expected, suggesting that sibutramine is associated with an increased cardiovascular risk in the study population,” the FDA noted.

Abbott started the study, Sibutramine Cardiovascular Morbidity/Mortality Outcomes in Overweight or Obese Subjects at Risk of a Cardiovascular Event (SCOUT), in 2002 at the request of the FDA's European counterpart, the European Medicines Agency (EMEA), as one of the conditions for keeping the drug on the market in Europe after serious cardiovascular events were reported in the early 2000s. The study's aim was to evaluate the safety and efficacy of sibutramine in overweight and obese people.

The FDA was apprised of the results in mid-November. On Dec. 3, Public Citizen's Health Research Group, a health advocacy organization, filed a citizen's petition calling on the FDA to withdraw the drug from the market immediately, because of the new data indicating that it increases the risk of MI, stroke, resuscitated cardiac arrest, or death.

In 2005, the FDA denied a previous petition by the group requesting that sibutramine be taken off the market because of concerns over its safety arising from preapproval clinical studies.

In an interview, Dr. Sidney Wolfe, director of the Washington-based Health Research Group, said that the preliminary results of the SCOUT trial are a concern. The group continues to support the withdrawal of sibutramine from the market and is analyzing sibutramine-related reports in the FDA's adverse event reporting system database, he said.

Despite the label's recommendation that patients with risk factors such as cardiovascular disease not be treated with sibutramine, the drug is still prescribed to patients who are obese and have some of these risk factors, he noted.

Report adverse events to the FDA's MedWatch program at 800-332-1088 or www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htmwww.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm191655.htm

The Food and Drug Administration is looking at recent data suggesting that the cardiovascular event rate among patients on the weight-loss drug sibutramine was higher than among those on placebo.

“The analysis of these data is ongoing and FDA is making no conclusions about the preliminary findings at this time,” according to a statement posted on the agency's MedWatch site. These findings, the statement adds, “highlight the importance of avoiding the use of sibutramine” in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or stroke, which is recommended in the current sibutramine label.

Sibutramine is an orally administered drug marketed as Meridia by Abbott Laboratories. Its therapeutic effects result from norepinephrine, serotonin, and dopamine reuptake inhibition, according to the label. It was approved in 1997 for the management of obesity in conjunction with a reduced-calorie diet, and is recommended only for obese patients with an initial body mass index at or above 30 kg/m

The FDA reported results from a study of about 10,000 overweight or obese patients aged 55 years or older who had a history of heart disease or type 2 diabetes and one additional cardiovascular risk factor. The preliminary results of the study's primary end point—MI, stroke, resuscitated cardiac arrest, or death—were reported in 11.4% of those on sibutramine, compared with 10% of those on placebo. The difference was “higher than expected, suggesting that sibutramine is associated with an increased cardiovascular risk in the study population,” the FDA noted.

Abbott started the study, Sibutramine Cardiovascular Morbidity/Mortality Outcomes in Overweight or Obese Subjects at Risk of a Cardiovascular Event (SCOUT), in 2002 at the request of the FDA's European counterpart, the European Medicines Agency (EMEA), as one of the conditions for keeping the drug on the market in Europe after serious cardiovascular events were reported in the early 2000s. The study's aim was to evaluate the safety and efficacy of sibutramine in overweight and obese people.

The FDA was apprised of the results in mid-November. On Dec. 3, Public Citizen's Health Research Group, a health advocacy organization, filed a citizen's petition calling on the FDA to withdraw the drug from the market immediately, because of the new data indicating that it increases the risk of MI, stroke, resuscitated cardiac arrest, or death.

In 2005, the FDA denied a previous petition by the group requesting that sibutramine be taken off the market because of concerns over its safety arising from preapproval clinical studies.

In an interview, Dr. Sidney Wolfe, director of the Washington-based Health Research Group, said that the preliminary results of the SCOUT trial are a concern. The group continues to support the withdrawal of sibutramine from the market and is analyzing sibutramine-related reports in the FDA's adverse event reporting system database, he said.

Despite the label's recommendation that patients with risk factors such as cardiovascular disease not be treated with sibutramine, the drug is still prescribed to patients who are obese and have some of these risk factors, he noted.

Report adverse events to the FDA's MedWatch program at 800-332-1088 or www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htmwww.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm191655.htm