Elizabeth Mechcatie

Concomitant use of low-dose aspirin and ibuprofen may interfere with aspirin's antiplatelet effects, possibly attenuating its cardioprotective benefits, according to a recent statement by the Food and Drug Administration's arm responsible for compiling adverse drug events.

“Platelet function tests suggest there is a pharmacodynamic interaction between 400 mg of ibuprofen and low-dose aspirin when they are dosed concomitantly,” the FDA wrote in a statement posted on its MedWatch Web site in September.

Experts stress, however, that virtually all nonsteroidal anti-inflammatory drugs have the potential to interfere with aspirin's cardioprotective effects. Compared with ibuprofen, there may be fewer data on the other NSAIDs, but “if physicians only pay attention to the FDA statement” they're likely to miss the potential effects of these other NSAIDs on aspirin's antiplatelet properties, said rheumatologist Dr. Roy Altman, of the University of California, Los Angeles.

The FDA's statement reinforces the importance of asking patients about over-the-counter drug usage. “Some colleagues may have let that mind-set go by the wayside,” said family physician Thomas A. Kintanar of Indiana University School of Medicine's Fort Wayne branch. It also doesn't hurt to focus on ibuprofen, which is one of the most widely used OTC drugs on the market.

Nevertheless, clinical studies have yet to be conducted to evaluate and quantify the inhibitory effect of ibuprofen on aspirin.

Nor are enough data available to address the effect of taking less than 400 mg of ibuprofen on aspirin's cardioprotective effects. And there are “no clear data” on the potential antiplatelet effects associated with the chronic use of ibuprofen at doses above 400 mg.

The FDA advised health care professionals to counsel patients taking immediate-release low-dose (81 mg) aspirin (not enteric coated) and 400 mg of ibuprofen to take the ibuprofen at least 8 hours before or at least 30 minutes after taking the aspirin to minimize the pharmacodynamic interaction. Other analgesics that do not interfere with aspirin's antiplatelet effects “should be considered” for patients at high risk for cardiovascular events. However, other nonselective, over-the-counter NSAIDs should also be considered as having the potential to affect the antiplatelet benefits of aspirin “unless proven otherwise.”

The recommendation on timing of the ibuprofen dose does not apply to patients taking enteric-coated low-dose aspirin, as such an advisement cannot be made based on the data available. Only one study showed that when 400 mg of ibuprofen is administered 2, 7, and 12 hours after enteric-coated low-dose aspirin, the antiplatelet effects are attenuated.

The mechanism underlying the aspirin-ibuprofen interaction may be due to “competitive inhibition of the acetylation site of cyclooxygenase in the platelet,” according to the FDA. Occasional use of ibuprofen, it said, is unlikely to have a negative impact on aspirin's cardioprotective effects because of the long-lasting effects of daily aspirin.

Dr. Raymond Gibbons, president of the American Heart Association (AHA), said in an interview that although the potential interaction between ibuprofen and aspirin has been recognized as a concern in the past, the advisory is a useful reminder to health care professionals about this issue.

These concerns are based on science that dates back to 2001, he said, adding that an AHA scientific advisory in the spring of 2005 on cyclooxygenase-2 inhibitors noted that data showed that ibuprofen interfered with aspirin and could possibly reduce the protective effects of aspirin.

He stressed the importance of the recommendation that analgesics that do not interfere with the antiplatelet effects of aspirin should be considered for high-risk patients. The data on ibuprofen are “far more suggestive of a problem” than, for example, data on acetaminophen or diclofenac, which are not associated with this risk, said Dr. Gibbons, the Albert M. and Gladys Gray professor of medicine at the Mayo Medical School, Rochester, Minn.

As for the recommendation on timing the ibuprofen and aspirin doses to avoid the interaction, Dr. Gibbons said he would be “cautious” about relying on appropriate timing, “because we don't have a tremendous amount of evidence in the presence of all the confounders” in patients. “I'd feel more comfortable if we emphasize the importance of this potential interaction and avoid ibuprofen in high-risk patients.”

Dr. Kintanar said he'd be comfortable allowing a compliant patient to follow the FDA's advice. However, it is rare to have that comfort level about a patient's level of compliance, he said.

For more information, go to www.fda.gov/medwatch/safety/2006/safety06.htm#aspirin

The warning reinforces the importance of asking patients about over-the-counter drug usage. DR. KINTANAR

Concomitant use of low-dose aspirin and ibuprofen may interfere with aspirin's antiplatelet effects, possibly attenuating its cardioprotective benefits, according to a recent statement by the Food and Drug Administration's arm responsible for compiling adverse drug events.

“Platelet function tests suggest there is a pharmacodynamic interaction between 400 mg of ibuprofen and low-dose aspirin when they are dosed concomitantly,” the FDA wrote in a statement posted on its MedWatch Web site in September.

Experts stress, however, that virtually all nonsteroidal anti-inflammatory drugs have the potential to interfere with aspirin's cardioprotective effects. Compared with ibuprofen, there may be fewer data on the other NSAIDs, but “if physicians only pay attention to the FDA statement” they're likely to miss the potential effects of these other NSAIDs on aspirin's antiplatelet properties, said rheumatologist Dr. Roy Altman, of the University of California, Los Angeles.

The FDA's statement reinforces the importance of asking patients about over-the-counter drug usage. “Some colleagues may have let that mind-set go by the wayside,” said family physician Thomas A. Kintanar of Indiana University School of Medicine's Fort Wayne branch. It also doesn't hurt to focus on ibuprofen, which is one of the most widely used OTC drugs on the market.

Nevertheless, clinical studies have yet to be conducted to evaluate and quantify the inhibitory effect of ibuprofen on aspirin.

Nor are enough data available to address the effect of taking less than 400 mg of ibuprofen on aspirin's cardioprotective effects. And there are “no clear data” on the potential antiplatelet effects associated with the chronic use of ibuprofen at doses above 400 mg.

The FDA advised health care professionals to counsel patients taking immediate-release low-dose (81 mg) aspirin (not enteric coated) and 400 mg of ibuprofen to take the ibuprofen at least 8 hours before or at least 30 minutes after taking the aspirin to minimize the pharmacodynamic interaction. Other analgesics that do not interfere with aspirin's antiplatelet effects “should be considered” for patients at high risk for cardiovascular events. However, other nonselective, over-the-counter NSAIDs should also be considered as having the potential to affect the antiplatelet benefits of aspirin “unless proven otherwise.”

The recommendation on timing of the ibuprofen dose does not apply to patients taking enteric-coated low-dose aspirin, as such an advisement cannot be made based on the data available. Only one study showed that when 400 mg of ibuprofen is administered 2, 7, and 12 hours after enteric-coated low-dose aspirin, the antiplatelet effects are attenuated.

The mechanism underlying the aspirin-ibuprofen interaction may be due to “competitive inhibition of the acetylation site of cyclooxygenase in the platelet,” according to the FDA. Occasional use of ibuprofen, it said, is unlikely to have a negative impact on aspirin's cardioprotective effects because of the long-lasting effects of daily aspirin.

Dr. Raymond Gibbons, president of the American Heart Association (AHA), said in an interview that although the potential interaction between ibuprofen and aspirin has been recognized as a concern in the past, the advisory is a useful reminder to health care professionals about this issue.

These concerns are based on science that dates back to 2001, he said, adding that an AHA scientific advisory in the spring of 2005 on cyclooxygenase-2 inhibitors noted that data showed that ibuprofen interfered with aspirin and could possibly reduce the protective effects of aspirin.

He stressed the importance of the recommendation that analgesics that do not interfere with the antiplatelet effects of aspirin should be considered for high-risk patients. The data on ibuprofen are “far more suggestive of a problem” than, for example, data on acetaminophen or diclofenac, which are not associated with this risk, said Dr. Gibbons, the Albert M. and Gladys Gray professor of medicine at the Mayo Medical School, Rochester, Minn.

As for the recommendation on timing the ibuprofen and aspirin doses to avoid the interaction, Dr. Gibbons said he would be “cautious” about relying on appropriate timing, “because we don't have a tremendous amount of evidence in the presence of all the confounders” in patients. “I'd feel more comfortable if we emphasize the importance of this potential interaction and avoid ibuprofen in high-risk patients.”

Dr. Kintanar said he'd be comfortable allowing a compliant patient to follow the FDA's advice. However, it is rare to have that comfort level about a patient's level of compliance, he said.

For more information, go to www.fda.gov/medwatch/safety/2006/safety06.htm#aspirin

The warning reinforces the importance of asking patients about over-the-counter drug usage. DR. KINTANAR

Concomitant use of low-dose aspirin and ibuprofen may interfere with aspirin's antiplatelet effects, possibly attenuating its cardioprotective benefits, according to a recent statement by the Food and Drug Administration's arm responsible for compiling adverse drug events.

“Platelet function tests suggest there is a pharmacodynamic interaction between 400 mg of ibuprofen and low-dose aspirin when they are dosed concomitantly,” the FDA wrote in a statement posted on its MedWatch Web site in September.

Experts stress, however, that virtually all nonsteroidal anti-inflammatory drugs have the potential to interfere with aspirin's cardioprotective effects. Compared with ibuprofen, there may be fewer data on the other NSAIDs, but “if physicians only pay attention to the FDA statement” they're likely to miss the potential effects of these other NSAIDs on aspirin's antiplatelet properties, said rheumatologist Dr. Roy Altman, of the University of California, Los Angeles.

The FDA's statement reinforces the importance of asking patients about over-the-counter drug usage. “Some colleagues may have let that mind-set go by the wayside,” said family physician Thomas A. Kintanar of Indiana University School of Medicine's Fort Wayne branch. It also doesn't hurt to focus on ibuprofen, which is one of the most widely used OTC drugs on the market.

Nevertheless, clinical studies have yet to be conducted to evaluate and quantify the inhibitory effect of ibuprofen on aspirin.

Nor are enough data available to address the effect of taking less than 400 mg of ibuprofen on aspirin's cardioprotective effects. And there are “no clear data” on the potential antiplatelet effects associated with the chronic use of ibuprofen at doses above 400 mg.

The FDA advised health care professionals to counsel patients taking immediate-release low-dose (81 mg) aspirin (not enteric coated) and 400 mg of ibuprofen to take the ibuprofen at least 8 hours before or at least 30 minutes after taking the aspirin to minimize the pharmacodynamic interaction. Other analgesics that do not interfere with aspirin's antiplatelet effects “should be considered” for patients at high risk for cardiovascular events. However, other nonselective, over-the-counter NSAIDs should also be considered as having the potential to affect the antiplatelet benefits of aspirin “unless proven otherwise.”

The recommendation on timing of the ibuprofen dose does not apply to patients taking enteric-coated low-dose aspirin, as such an advisement cannot be made based on the data available. Only one study showed that when 400 mg of ibuprofen is administered 2, 7, and 12 hours after enteric-coated low-dose aspirin, the antiplatelet effects are attenuated.

The mechanism underlying the aspirin-ibuprofen interaction may be due to “competitive inhibition of the acetylation site of cyclooxygenase in the platelet,” according to the FDA. Occasional use of ibuprofen, it said, is unlikely to have a negative impact on aspirin's cardioprotective effects because of the long-lasting effects of daily aspirin.

Dr. Raymond Gibbons, president of the American Heart Association (AHA), said in an interview that although the potential interaction between ibuprofen and aspirin has been recognized as a concern in the past, the advisory is a useful reminder to health care professionals about this issue.

These concerns are based on science that dates back to 2001, he said, adding that an AHA scientific advisory in the spring of 2005 on cyclooxygenase-2 inhibitors noted that data showed that ibuprofen interfered with aspirin and could possibly reduce the protective effects of aspirin.

He stressed the importance of the recommendation that analgesics that do not interfere with the antiplatelet effects of aspirin should be considered for high-risk patients. The data on ibuprofen are “far more suggestive of a problem” than, for example, data on acetaminophen or diclofenac, which are not associated with this risk, said Dr. Gibbons, the Albert M. and Gladys Gray professor of medicine at the Mayo Medical School, Rochester, Minn.

As for the recommendation on timing the ibuprofen and aspirin doses to avoid the interaction, Dr. Gibbons said he would be “cautious” about relying on appropriate timing, “because we don't have a tremendous amount of evidence in the presence of all the confounders” in patients. “I'd feel more comfortable if we emphasize the importance of this potential interaction and avoid ibuprofen in high-risk patients.”

Dr. Kintanar said he'd be comfortable allowing a compliant patient to follow the FDA's advice. However, it is rare to have that comfort level about a patient's level of compliance, he said.

For more information, go to www.fda.gov/medwatch/safety/2006/safety06.htm#aspirin

The warning reinforces the importance of asking patients about over-the-counter drug usage. DR. KINTANAR

A federal judge has ordered the manufacturer of generic clopidogrel to stop selling the product but not to recall the stock that remains in pharmacies, which, according to the ruling, had been used to fill almost 80% of clopidogrel prescriptions.

On Aug. 31, the U.S. District Court for the Southern District of New York granted the motion filed by Sanofi-Aventis requesting a preliminary injunction that prohibits the Canadian generic manufacturer, Apotex Inc., from selling its generic formulation of clopidogrel, until a patent infringement case filed against Apotex is resolved. The court, however, did not order Apotex to recall the generic clopidogrel product that has already been distributed.

In early August, Apotex launched its generic clopidogrel amid patent litigation with marketers of clopidogrel (Plavix), Bristol-Myers Squibb Co. (BMS) and Sanofi-Aventis, and a federal investigation of the latter companies.

The generic clopidogrel was used to fill most prescriptions. BMS and Sanofi-Aventis moved for a preliminary injunction in U.S. District Court for the Southern District of New York ordering Apotex to halt sales and recall existing inventory, and a hearing was held on Aug. 18.

The court's opinion stated that Sanofi had “adequately demonstrated” that questions Apotex raised about the validity and enforceability of the clopidogrel patent were “without substantial merit” based on the evidence to date, and that Sanofi had “demonstrated a likelihood of success on the merits at trial.” The Court also ordered Sanofi and BMS to post a $400 million bond, as security for Apotex in case the final ruling favored the generic company. A trial date has been set for Jan. 22, 2007.

At the time of the hearing, one generic clopidogrel pill cost $1.10 less than the price of one Plavix pill before Apotex launched the generic, and 78.4% of all clopidogrel prescriptions were being filled with the generic product, according to the opinion. The document refers to testimony made at the hearing that there were 48 million people who used clopidogrel daily.

A federal judge has ordered the manufacturer of generic clopidogrel to stop selling the product but not to recall the stock that remains in pharmacies, which, according to the ruling, had been used to fill almost 80% of clopidogrel prescriptions.

On Aug. 31, the U.S. District Court for the Southern District of New York granted the motion filed by Sanofi-Aventis requesting a preliminary injunction that prohibits the Canadian generic manufacturer, Apotex Inc., from selling its generic formulation of clopidogrel, until a patent infringement case filed against Apotex is resolved. The court, however, did not order Apotex to recall the generic clopidogrel product that has already been distributed.

In early August, Apotex launched its generic clopidogrel amid patent litigation with marketers of clopidogrel (Plavix), Bristol-Myers Squibb Co. (BMS) and Sanofi-Aventis, and a federal investigation of the latter companies.

The generic clopidogrel was used to fill most prescriptions. BMS and Sanofi-Aventis moved for a preliminary injunction in U.S. District Court for the Southern District of New York ordering Apotex to halt sales and recall existing inventory, and a hearing was held on Aug. 18.

The court's opinion stated that Sanofi had “adequately demonstrated” that questions Apotex raised about the validity and enforceability of the clopidogrel patent were “without substantial merit” based on the evidence to date, and that Sanofi had “demonstrated a likelihood of success on the merits at trial.” The Court also ordered Sanofi and BMS to post a $400 million bond, as security for Apotex in case the final ruling favored the generic company. A trial date has been set for Jan. 22, 2007.

At the time of the hearing, one generic clopidogrel pill cost $1.10 less than the price of one Plavix pill before Apotex launched the generic, and 78.4% of all clopidogrel prescriptions were being filled with the generic product, according to the opinion. The document refers to testimony made at the hearing that there were 48 million people who used clopidogrel daily.

A federal judge has ordered the manufacturer of generic clopidogrel to stop selling the product but not to recall the stock that remains in pharmacies, which, according to the ruling, had been used to fill almost 80% of clopidogrel prescriptions.

On Aug. 31, the U.S. District Court for the Southern District of New York granted the motion filed by Sanofi-Aventis requesting a preliminary injunction that prohibits the Canadian generic manufacturer, Apotex Inc., from selling its generic formulation of clopidogrel, until a patent infringement case filed against Apotex is resolved. The court, however, did not order Apotex to recall the generic clopidogrel product that has already been distributed.

In early August, Apotex launched its generic clopidogrel amid patent litigation with marketers of clopidogrel (Plavix), Bristol-Myers Squibb Co. (BMS) and Sanofi-Aventis, and a federal investigation of the latter companies.

The generic clopidogrel was used to fill most prescriptions. BMS and Sanofi-Aventis moved for a preliminary injunction in U.S. District Court for the Southern District of New York ordering Apotex to halt sales and recall existing inventory, and a hearing was held on Aug. 18.

The court's opinion stated that Sanofi had “adequately demonstrated” that questions Apotex raised about the validity and enforceability of the clopidogrel patent were “without substantial merit” based on the evidence to date, and that Sanofi had “demonstrated a likelihood of success on the merits at trial.” The Court also ordered Sanofi and BMS to post a $400 million bond, as security for Apotex in case the final ruling favored the generic company. A trial date has been set for Jan. 22, 2007.

At the time of the hearing, one generic clopidogrel pill cost $1.10 less than the price of one Plavix pill before Apotex launched the generic, and 78.4% of all clopidogrel prescriptions were being filled with the generic product, according to the opinion. The document refers to testimony made at the hearing that there were 48 million people who used clopidogrel daily.

A temporary shortage in the supply of Adacel—the tetanus-diphtheria-pertussis vaccine marketed by Sanofi-Pasteur—announced in September is expected to last until the end of the year.

Boostrix, the Tdap booster vaccine manufactured by GlaxoSmithKline, is in good supply, according to the Centers for Disease Control and Prevention. Adacel (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed) is indicated as a booster for adolescents and adults aged 11–64 years, while Boostrix is indicated for adolescents aged 10–18 years.

For information about Adacel availability, call Sanofi-Pasteur at 800-VACCINE.

The supply shortage of Adacel is expected to be resolved by the end of this year, said Susan Watkins, a spokesperson for Sanofi-Pasteur.

A new vaccine production facility in Toronto that will provide a sevenfold increase of the supply of vaccines with pertussis components was approved by the Food and Drug Administration in late August. It has already started to manufacture the DTaP vaccine Daptacel, and will begin producing Adacel next.

In the meantime, Adacel is being manufactured in another facility, but not in large enough quantities to meet the demand, she added.

Dr. Jack Swanson, a pediatrician in Ames, Iowa, said in an interview that his practice had temporarily switched to Boostrix, but would probably resume using Adacel when it became available because he practices in a multispeciality clinic where adults are also treated.

Dr. H. Garry Gardner, a pediatrician in Darien, Ill., said in an interview that his practice was already using Boostrix without any problems.

Updates on the Adacel shortage will be provided on the CDC Web site at www.cdc.gov/nip/news/shortages/default.htm

A temporary shortage in the supply of Adacel—the tetanus-diphtheria-pertussis vaccine marketed by Sanofi-Pasteur—announced in September is expected to last until the end of the year.

Boostrix, the Tdap booster vaccine manufactured by GlaxoSmithKline, is in good supply, according to the Centers for Disease Control and Prevention. Adacel (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed) is indicated as a booster for adolescents and adults aged 11–64 years, while Boostrix is indicated for adolescents aged 10–18 years.

For information about Adacel availability, call Sanofi-Pasteur at 800-VACCINE.

The supply shortage of Adacel is expected to be resolved by the end of this year, said Susan Watkins, a spokesperson for Sanofi-Pasteur.

A new vaccine production facility in Toronto that will provide a sevenfold increase of the supply of vaccines with pertussis components was approved by the Food and Drug Administration in late August. It has already started to manufacture the DTaP vaccine Daptacel, and will begin producing Adacel next.

In the meantime, Adacel is being manufactured in another facility, but not in large enough quantities to meet the demand, she added.

Dr. Jack Swanson, a pediatrician in Ames, Iowa, said in an interview that his practice had temporarily switched to Boostrix, but would probably resume using Adacel when it became available because he practices in a multispeciality clinic where adults are also treated.

Dr. H. Garry Gardner, a pediatrician in Darien, Ill., said in an interview that his practice was already using Boostrix without any problems.

Updates on the Adacel shortage will be provided on the CDC Web site at www.cdc.gov/nip/news/shortages/default.htm

A temporary shortage in the supply of Adacel—the tetanus-diphtheria-pertussis vaccine marketed by Sanofi-Pasteur—announced in September is expected to last until the end of the year.

Boostrix, the Tdap booster vaccine manufactured by GlaxoSmithKline, is in good supply, according to the Centers for Disease Control and Prevention. Adacel (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed) is indicated as a booster for adolescents and adults aged 11–64 years, while Boostrix is indicated for adolescents aged 10–18 years.

For information about Adacel availability, call Sanofi-Pasteur at 800-VACCINE.

The supply shortage of Adacel is expected to be resolved by the end of this year, said Susan Watkins, a spokesperson for Sanofi-Pasteur.

A new vaccine production facility in Toronto that will provide a sevenfold increase of the supply of vaccines with pertussis components was approved by the Food and Drug Administration in late August. It has already started to manufacture the DTaP vaccine Daptacel, and will begin producing Adacel next.

In the meantime, Adacel is being manufactured in another facility, but not in large enough quantities to meet the demand, she added.

Dr. Jack Swanson, a pediatrician in Ames, Iowa, said in an interview that his practice had temporarily switched to Boostrix, but would probably resume using Adacel when it became available because he practices in a multispeciality clinic where adults are also treated.

Dr. H. Garry Gardner, a pediatrician in Darien, Ill., said in an interview that his practice was already using Boostrix without any problems.

Updates on the Adacel shortage will be provided on the CDC Web site at www.cdc.gov/nip/news/shortages/default.htm

The first generic formulation of the antidepressant venlafaxine has been approved by the Food and Drug Administration.

The FDA announced in early August that it had approved the generic version of the immediate-release formulation of Effexor in 25-mg, 37.5-mg, 50-mg, 75-mg, and 100-mg tablets, the same doses available for Effexor. The generic manufacturer, Teva Pharmaceuticals USA, announced that shipment of the tablets would start immediately.

Teva has exclusive rights to market the generic formulation for 180 days after approval, after which time the FDA can approve applications for other generic formulations of venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI).

Effexor, marketed by Wyeth Pharmaceuticals Inc., was approved for major depressive disorder in 1993; the extended-release formulation (Effexor XR) was approved in 1997.

Other recently approved first-time generic drugs include escitalopram tablets, the generic version of the selective serotonin reuptake inhibitor (SSRI) Lexapro, and sertraline in tablet and oral concentrate formulations, the generic version of the SSRI Zoloft.

The first generic formulation of the antidepressant venlafaxine has been approved by the Food and Drug Administration.

The FDA announced in early August that it had approved the generic version of the immediate-release formulation of Effexor in 25-mg, 37.5-mg, 50-mg, 75-mg, and 100-mg tablets, the same doses available for Effexor. The generic manufacturer, Teva Pharmaceuticals USA, announced that shipment of the tablets would start immediately.

Teva has exclusive rights to market the generic formulation for 180 days after approval, after which time the FDA can approve applications for other generic formulations of venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI).

Effexor, marketed by Wyeth Pharmaceuticals Inc., was approved for major depressive disorder in 1993; the extended-release formulation (Effexor XR) was approved in 1997.

Other recently approved first-time generic drugs include escitalopram tablets, the generic version of the selective serotonin reuptake inhibitor (SSRI) Lexapro, and sertraline in tablet and oral concentrate formulations, the generic version of the SSRI Zoloft.

The first generic formulation of the antidepressant venlafaxine has been approved by the Food and Drug Administration.

The FDA announced in early August that it had approved the generic version of the immediate-release formulation of Effexor in 25-mg, 37.5-mg, 50-mg, 75-mg, and 100-mg tablets, the same doses available for Effexor. The generic manufacturer, Teva Pharmaceuticals USA, announced that shipment of the tablets would start immediately.

Teva has exclusive rights to market the generic formulation for 180 days after approval, after which time the FDA can approve applications for other generic formulations of venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI).

Effexor, marketed by Wyeth Pharmaceuticals Inc., was approved for major depressive disorder in 1993; the extended-release formulation (Effexor XR) was approved in 1997.

Other recently approved first-time generic drugs include escitalopram tablets, the generic version of the selective serotonin reuptake inhibitor (SSRI) Lexapro, and sertraline in tablet and oral concentrate formulations, the generic version of the SSRI Zoloft.

Concerns that nonsteroidal anti-inflammatory drugs can interfere with aspirin's cardioprotective effects received new attention following a Food and Drug Administration warning about concomitant use of low-dose aspirin and ibuprofen.

Ibuprofen can interfere with aspirin's antiplatelet effects, according to a statement issued by the Food and Drug Administration's arm responsible for compiling adverse drug events.

“Platelet function tests suggest there is a pharmacodynamic interaction between 400 mg of ibuprofen and low-dose aspirin when they are dosed concomitantly,” the FDA said in a paper posted on its MedWatch Web site in September.

Experts stress, however, that although there may be fewer data on the other NSAIDs, “if physicians only pay attention to the FDA statement,” they're likely to miss the potential effects of these other NSAIDs on aspirin's antiplatelet properties and focus only on ibuprofen, said rheumatologist Dr. Roy Altman, of the University of California, Los Angeles.

Nevertheless, clinical studies have yet to be conducted to evaluate and quantify the inhibitory effect of ibuprofen on aspirin. Not enough data are available to address the effect of taking less than 400 mg of ibuprofen on aspirin's cardioprotective benefits. Nor are there “clear data” on the potential antiplatelet effects associated with chronic use of ibuprofen at doses above 400 mg, the FDA said in the statement.

The FDA advised health care professionals to counsel patients taking immediate-release low-dose (81 mg) aspirin (not enteric coated) and 400 mg of ibuprofen to take the ibuprofen at least 8 hours before or at least 30 minutes after taking the aspirin, which can minimize the pharmacodynamic interaction.

The mechanism underlying the aspirin-ibuprofen interaction may be due to “competitive inhibition of the acetylation site of cyclooxygenase in the platelet,” according to the FDA statement.

Occasional use of ibuprofen, the FDA said, is unlikely to have a negative impact on aspirin's cardioprotective effects because of the long-lasting effects of daily aspirin.

In an interview, Dr. Raymond Gibbons, president of the American Heart Association (AHA), said that although the potential interaction between ibuprofen and aspirin has been recognized as a concern in the past, the FDA advisory is a useful reminder to health care professionals about this important issue.

These concerns are based on science that dates back to 2001, Dr. Gibbons said, adding that an AHA scientific advisory in the spring of 2005 on cyclooxygenase-2 inhibitors noted that data indicated ibuprofen interfered with aspirin, and could possibly reduce the protective effects of aspirin.

He emphasized the importance of the FDA's recommendation that analgesics that do not interfere with the antiplatelet effects of aspirin should be considered for high-risk patients. The data on ibuprofen are “far more suggestive of a problem” than, for example, data on acetaminophen or diclofenac, which are not associated with this risk, said Dr. Gibbons, who is the Albert M. and Gladys Gray professor of medicine at the Mayo Medical School, Rochester, Minn.

As for the recommendation on appropriate timing of ibuprofen and aspirin to avoid the interaction, he said he would be “cautious” about relying on appropriate timing, “simply because we don't have a tremendous amount of evidence in the presence of all the confounders” in patients. “I would feel more comfortable if we emphasize the importance of this potential interaction and avoid ibuprofen in high-risk patients,” Dr. Gibbons said.

Regarding cardiovascular health targets, a far greater problem is that the many candidates for aspirin are not taking it.

The notice is on the FDA's MedWatch site at www.fda.gov/medwatch/safety/2006/safety06.htm#aspirin

Rather than timing dosages, 'I would feel more comfortable if we … avoid ibuprofen in high-risk patients.' DR. GIBBONS

Concerns that nonsteroidal anti-inflammatory drugs can interfere with aspirin's cardioprotective effects received new attention following a Food and Drug Administration warning about concomitant use of low-dose aspirin and ibuprofen.

Ibuprofen can interfere with aspirin's antiplatelet effects, according to a statement issued by the Food and Drug Administration's arm responsible for compiling adverse drug events.

“Platelet function tests suggest there is a pharmacodynamic interaction between 400 mg of ibuprofen and low-dose aspirin when they are dosed concomitantly,” the FDA said in a paper posted on its MedWatch Web site in September.

Experts stress, however, that although there may be fewer data on the other NSAIDs, “if physicians only pay attention to the FDA statement,” they're likely to miss the potential effects of these other NSAIDs on aspirin's antiplatelet properties and focus only on ibuprofen, said rheumatologist Dr. Roy Altman, of the University of California, Los Angeles.

Nevertheless, clinical studies have yet to be conducted to evaluate and quantify the inhibitory effect of ibuprofen on aspirin. Not enough data are available to address the effect of taking less than 400 mg of ibuprofen on aspirin's cardioprotective benefits. Nor are there “clear data” on the potential antiplatelet effects associated with chronic use of ibuprofen at doses above 400 mg, the FDA said in the statement.

The FDA advised health care professionals to counsel patients taking immediate-release low-dose (81 mg) aspirin (not enteric coated) and 400 mg of ibuprofen to take the ibuprofen at least 8 hours before or at least 30 minutes after taking the aspirin, which can minimize the pharmacodynamic interaction.

The mechanism underlying the aspirin-ibuprofen interaction may be due to “competitive inhibition of the acetylation site of cyclooxygenase in the platelet,” according to the FDA statement.

Occasional use of ibuprofen, the FDA said, is unlikely to have a negative impact on aspirin's cardioprotective effects because of the long-lasting effects of daily aspirin.

In an interview, Dr. Raymond Gibbons, president of the American Heart Association (AHA), said that although the potential interaction between ibuprofen and aspirin has been recognized as a concern in the past, the FDA advisory is a useful reminder to health care professionals about this important issue.

These concerns are based on science that dates back to 2001, Dr. Gibbons said, adding that an AHA scientific advisory in the spring of 2005 on cyclooxygenase-2 inhibitors noted that data indicated ibuprofen interfered with aspirin, and could possibly reduce the protective effects of aspirin.

He emphasized the importance of the FDA's recommendation that analgesics that do not interfere with the antiplatelet effects of aspirin should be considered for high-risk patients. The data on ibuprofen are “far more suggestive of a problem” than, for example, data on acetaminophen or diclofenac, which are not associated with this risk, said Dr. Gibbons, who is the Albert M. and Gladys Gray professor of medicine at the Mayo Medical School, Rochester, Minn.

As for the recommendation on appropriate timing of ibuprofen and aspirin to avoid the interaction, he said he would be “cautious” about relying on appropriate timing, “simply because we don't have a tremendous amount of evidence in the presence of all the confounders” in patients. “I would feel more comfortable if we emphasize the importance of this potential interaction and avoid ibuprofen in high-risk patients,” Dr. Gibbons said.

Regarding cardiovascular health targets, a far greater problem is that the many candidates for aspirin are not taking it.

The notice is on the FDA's MedWatch site at www.fda.gov/medwatch/safety/2006/safety06.htm#aspirin

Rather than timing dosages, 'I would feel more comfortable if we … avoid ibuprofen in high-risk patients.' DR. GIBBONS

Concerns that nonsteroidal anti-inflammatory drugs can interfere with aspirin's cardioprotective effects received new attention following a Food and Drug Administration warning about concomitant use of low-dose aspirin and ibuprofen.

Ibuprofen can interfere with aspirin's antiplatelet effects, according to a statement issued by the Food and Drug Administration's arm responsible for compiling adverse drug events.

“Platelet function tests suggest there is a pharmacodynamic interaction between 400 mg of ibuprofen and low-dose aspirin when they are dosed concomitantly,” the FDA said in a paper posted on its MedWatch Web site in September.

Experts stress, however, that although there may be fewer data on the other NSAIDs, “if physicians only pay attention to the FDA statement,” they're likely to miss the potential effects of these other NSAIDs on aspirin's antiplatelet properties and focus only on ibuprofen, said rheumatologist Dr. Roy Altman, of the University of California, Los Angeles.

Nevertheless, clinical studies have yet to be conducted to evaluate and quantify the inhibitory effect of ibuprofen on aspirin. Not enough data are available to address the effect of taking less than 400 mg of ibuprofen on aspirin's cardioprotective benefits. Nor are there “clear data” on the potential antiplatelet effects associated with chronic use of ibuprofen at doses above 400 mg, the FDA said in the statement.

The FDA advised health care professionals to counsel patients taking immediate-release low-dose (81 mg) aspirin (not enteric coated) and 400 mg of ibuprofen to take the ibuprofen at least 8 hours before or at least 30 minutes after taking the aspirin, which can minimize the pharmacodynamic interaction.

The mechanism underlying the aspirin-ibuprofen interaction may be due to “competitive inhibition of the acetylation site of cyclooxygenase in the platelet,” according to the FDA statement.

Occasional use of ibuprofen, the FDA said, is unlikely to have a negative impact on aspirin's cardioprotective effects because of the long-lasting effects of daily aspirin.

In an interview, Dr. Raymond Gibbons, president of the American Heart Association (AHA), said that although the potential interaction between ibuprofen and aspirin has been recognized as a concern in the past, the FDA advisory is a useful reminder to health care professionals about this important issue.

These concerns are based on science that dates back to 2001, Dr. Gibbons said, adding that an AHA scientific advisory in the spring of 2005 on cyclooxygenase-2 inhibitors noted that data indicated ibuprofen interfered with aspirin, and could possibly reduce the protective effects of aspirin.

He emphasized the importance of the FDA's recommendation that analgesics that do not interfere with the antiplatelet effects of aspirin should be considered for high-risk patients. The data on ibuprofen are “far more suggestive of a problem” than, for example, data on acetaminophen or diclofenac, which are not associated with this risk, said Dr. Gibbons, who is the Albert M. and Gladys Gray professor of medicine at the Mayo Medical School, Rochester, Minn.

As for the recommendation on appropriate timing of ibuprofen and aspirin to avoid the interaction, he said he would be “cautious” about relying on appropriate timing, “simply because we don't have a tremendous amount of evidence in the presence of all the confounders” in patients. “I would feel more comfortable if we emphasize the importance of this potential interaction and avoid ibuprofen in high-risk patients,” Dr. Gibbons said.

Regarding cardiovascular health targets, a far greater problem is that the many candidates for aspirin are not taking it.

The notice is on the FDA's MedWatch site at www.fda.gov/medwatch/safety/2006/safety06.htm#aspirin

Rather than timing dosages, 'I would feel more comfortable if we … avoid ibuprofen in high-risk patients.' DR. GIBBONS

Warnings about sudden death, exacerbation of psychiatric illnesses, and other risks associated with dextroamphetamine use have been added to the drug's label and are highlighted in a “dear health care professional” letter issued by the drug's manufacturer last month.

In the letter, which was dated Aug. 4, 2006, GlaxoSmithKline (GSK) noted that a black box warning in the label has been updated to include the statement that “misuse of amphetamines may cause sudden death and serious cardiovascular events.”

GSK manufactures Dexedrine (dextroamphetamine sulfate) Spansule sustained-release capsules and tablets. Dexedrine is approved by the Food and Drug Administration for treating attention-deficit hyperactivity disorder in pediatric patients, and for narcolepsy.

The warnings section also has been updated to include information about the cardiovascular and psychiatric events that have been associated with dextroamphetamine and other central nervous system stimulants.

These revisions were made after the FDA requested that all manufacturers of CNS stimulants approved for ADHD add standardized language in the prescribing information about these risks. This action was taken in response to recommendations made by two FDA advisory panels earlier this year.

The revised warning about serious cardiovascular deaths notes that sudden death has been reported in association with usual dosages of CNS stimulants in children and adolescents with structural cardiac abnormalities or other serious heart problems.

These drugs generally should not be used in children or adolescents with “known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems,” which may make them more vulnerable to the sympathomimetic effects of stimulants, according to the warning.

The warning also notes that sudden death, stroke, and myocardial infarctions have been reported in adults on usual ADHD drug doses, and that although the role of the stimulants in these cases is unknown, adults are at greater risk than are children of having serious cardiac problems such as cardiomyopathy.

Those patients known to have such cardiac abnormalities “should also generally not be treated with stimulant drugs,” according to the dear health care professional letter.

The warning recommends that children, adolescents, or adults being considered for stimulant treatment undergo a careful history that includes assessment for a family history of sudden death or ventricular arrhythmia, and physical exam to evaluate for cardiac disease, and “should receive further cardiac evaluation if findings suggest such disease.”

Also highlighted in the dear health care professional letter is information from the label on psychiatric adverse events, including statements that stimulants may exacerbate symptoms in people with a preexisting psychotic disorder and can cause the appearance of treatment emergent psychotic or manic symptoms in children and adolescents with no previous history.

The label information also notes that aggressive behavior or hostility has been associated with some drugs used to treat ADHD.

A copy of the letter and the revised label can be found at www.fda.gov/medwatch/safety/2006/safety06.htm#Dexedrinewww.fda.gov/medwatch

Warnings about sudden death, exacerbation of psychiatric illnesses, and other risks associated with dextroamphetamine use have been added to the drug's label and are highlighted in a “dear health care professional” letter issued by the drug's manufacturer last month.

In the letter, which was dated Aug. 4, 2006, GlaxoSmithKline (GSK) noted that a black box warning in the label has been updated to include the statement that “misuse of amphetamines may cause sudden death and serious cardiovascular events.”

GSK manufactures Dexedrine (dextroamphetamine sulfate) Spansule sustained-release capsules and tablets. Dexedrine is approved by the Food and Drug Administration for treating attention-deficit hyperactivity disorder in pediatric patients, and for narcolepsy.

The warnings section also has been updated to include information about the cardiovascular and psychiatric events that have been associated with dextroamphetamine and other central nervous system stimulants.

These revisions were made after the FDA requested that all manufacturers of CNS stimulants approved for ADHD add standardized language in the prescribing information about these risks. This action was taken in response to recommendations made by two FDA advisory panels earlier this year.

The revised warning about serious cardiovascular deaths notes that sudden death has been reported in association with usual dosages of CNS stimulants in children and adolescents with structural cardiac abnormalities or other serious heart problems.

These drugs generally should not be used in children or adolescents with “known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems,” which may make them more vulnerable to the sympathomimetic effects of stimulants, according to the warning.

The warning also notes that sudden death, stroke, and myocardial infarctions have been reported in adults on usual ADHD drug doses, and that although the role of the stimulants in these cases is unknown, adults are at greater risk than are children of having serious cardiac problems such as cardiomyopathy.

Those patients known to have such cardiac abnormalities “should also generally not be treated with stimulant drugs,” according to the dear health care professional letter.

The warning recommends that children, adolescents, or adults being considered for stimulant treatment undergo a careful history that includes assessment for a family history of sudden death or ventricular arrhythmia, and physical exam to evaluate for cardiac disease, and “should receive further cardiac evaluation if findings suggest such disease.”

Also highlighted in the dear health care professional letter is information from the label on psychiatric adverse events, including statements that stimulants may exacerbate symptoms in people with a preexisting psychotic disorder and can cause the appearance of treatment emergent psychotic or manic symptoms in children and adolescents with no previous history.

The label information also notes that aggressive behavior or hostility has been associated with some drugs used to treat ADHD.

A copy of the letter and the revised label can be found at www.fda.gov/medwatch/safety/2006/safety06.htm#Dexedrinewww.fda.gov/medwatch

Warnings about sudden death, exacerbation of psychiatric illnesses, and other risks associated with dextroamphetamine use have been added to the drug's label and are highlighted in a “dear health care professional” letter issued by the drug's manufacturer last month.

In the letter, which was dated Aug. 4, 2006, GlaxoSmithKline (GSK) noted that a black box warning in the label has been updated to include the statement that “misuse of amphetamines may cause sudden death and serious cardiovascular events.”

GSK manufactures Dexedrine (dextroamphetamine sulfate) Spansule sustained-release capsules and tablets. Dexedrine is approved by the Food and Drug Administration for treating attention-deficit hyperactivity disorder in pediatric patients, and for narcolepsy.

The warnings section also has been updated to include information about the cardiovascular and psychiatric events that have been associated with dextroamphetamine and other central nervous system stimulants.

These revisions were made after the FDA requested that all manufacturers of CNS stimulants approved for ADHD add standardized language in the prescribing information about these risks. This action was taken in response to recommendations made by two FDA advisory panels earlier this year.

The revised warning about serious cardiovascular deaths notes that sudden death has been reported in association with usual dosages of CNS stimulants in children and adolescents with structural cardiac abnormalities or other serious heart problems.

These drugs generally should not be used in children or adolescents with “known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems,” which may make them more vulnerable to the sympathomimetic effects of stimulants, according to the warning.

The warning also notes that sudden death, stroke, and myocardial infarctions have been reported in adults on usual ADHD drug doses, and that although the role of the stimulants in these cases is unknown, adults are at greater risk than are children of having serious cardiac problems such as cardiomyopathy.

Those patients known to have such cardiac abnormalities “should also generally not be treated with stimulant drugs,” according to the dear health care professional letter.

The warning recommends that children, adolescents, or adults being considered for stimulant treatment undergo a careful history that includes assessment for a family history of sudden death or ventricular arrhythmia, and physical exam to evaluate for cardiac disease, and “should receive further cardiac evaluation if findings suggest such disease.”

Also highlighted in the dear health care professional letter is information from the label on psychiatric adverse events, including statements that stimulants may exacerbate symptoms in people with a preexisting psychotic disorder and can cause the appearance of treatment emergent psychotic or manic symptoms in children and adolescents with no previous history.

The label information also notes that aggressive behavior or hostility has been associated with some drugs used to treat ADHD.

A copy of the letter and the revised label can be found at www.fda.gov/medwatch/safety/2006/safety06.htm#Dexedrinewww.fda.gov/medwatch

A study that evaluated children with severe juvenile idiopathic arthritis before and after starting anti-tumor necrosis factor treatment indicated that these biological agents appear to be effective in restoring normal growth in this population, reported Dr. Pirjo Tynjälä.

The results also suggest that the improvements in growth are related to the impact these treatments have on inflammation, wrote Dr. Tynjälä of the Hospital for Children and Adolescents, Helsinki University Central Hospital, and her associates (Ann. Rheum. Dis. 2006;65: 1044–9).

The study followed the growth of 71 children with polyarticular disease-course juvenile idiopathic arthritis for 2 years before and 2 years after starting etanercept (43 patients) or infliximab (28 patients). When treatment started, mean age was 9.6 years, mean disease duration was 5.7 years, and the children were refractory to conventional disease-modifying antirheumatic drugs. The dose of etanercept (Enbrel) was 0.4 mg/kg twice a week; the dose of infliximab (Remicade) was 80–200 mg every 6–8 weeks administered intravenously.

In the group overall, the mean growth velocity increased significantly during treatment, which was mostly because of the increase in the 53 children whose growth was delayed before starting treatment. Among the 18 children whose growth was normal or accelerated before treatment, growth velocity increased, but not significantly, during treatment. Over the 4 years, there were no significant differences in the total steroid dose among those with delayed growth and those with normal growth.

After 24 months of treatment, disease was inactive in 52% of the patients, and activity had decreased in the remainder, Dr. Tynjälä and her colleagues wrote.

The change in inflammatory activity “remained a significant predictor of the growth velocity, even after glucocorticoids were taken into account,” suggesting that the improved growth velocity may be because of the reduction in inflammation and not “a direct effect of biological agents on growth or on skeletal maturation.”

A study that evaluated children with severe juvenile idiopathic arthritis before and after starting anti-tumor necrosis factor treatment indicated that these biological agents appear to be effective in restoring normal growth in this population, reported Dr. Pirjo Tynjälä.

The results also suggest that the improvements in growth are related to the impact these treatments have on inflammation, wrote Dr. Tynjälä of the Hospital for Children and Adolescents, Helsinki University Central Hospital, and her associates (Ann. Rheum. Dis. 2006;65: 1044–9).

The study followed the growth of 71 children with polyarticular disease-course juvenile idiopathic arthritis for 2 years before and 2 years after starting etanercept (43 patients) or infliximab (28 patients). When treatment started, mean age was 9.6 years, mean disease duration was 5.7 years, and the children were refractory to conventional disease-modifying antirheumatic drugs. The dose of etanercept (Enbrel) was 0.4 mg/kg twice a week; the dose of infliximab (Remicade) was 80–200 mg every 6–8 weeks administered intravenously.

In the group overall, the mean growth velocity increased significantly during treatment, which was mostly because of the increase in the 53 children whose growth was delayed before starting treatment. Among the 18 children whose growth was normal or accelerated before treatment, growth velocity increased, but not significantly, during treatment. Over the 4 years, there were no significant differences in the total steroid dose among those with delayed growth and those with normal growth.

After 24 months of treatment, disease was inactive in 52% of the patients, and activity had decreased in the remainder, Dr. Tynjälä and her colleagues wrote.

The change in inflammatory activity “remained a significant predictor of the growth velocity, even after glucocorticoids were taken into account,” suggesting that the improved growth velocity may be because of the reduction in inflammation and not “a direct effect of biological agents on growth or on skeletal maturation.”

A study that evaluated children with severe juvenile idiopathic arthritis before and after starting anti-tumor necrosis factor treatment indicated that these biological agents appear to be effective in restoring normal growth in this population, reported Dr. Pirjo Tynjälä.

The results also suggest that the improvements in growth are related to the impact these treatments have on inflammation, wrote Dr. Tynjälä of the Hospital for Children and Adolescents, Helsinki University Central Hospital, and her associates (Ann. Rheum. Dis. 2006;65: 1044–9).

The study followed the growth of 71 children with polyarticular disease-course juvenile idiopathic arthritis for 2 years before and 2 years after starting etanercept (43 patients) or infliximab (28 patients). When treatment started, mean age was 9.6 years, mean disease duration was 5.7 years, and the children were refractory to conventional disease-modifying antirheumatic drugs. The dose of etanercept (Enbrel) was 0.4 mg/kg twice a week; the dose of infliximab (Remicade) was 80–200 mg every 6–8 weeks administered intravenously.

In the group overall, the mean growth velocity increased significantly during treatment, which was mostly because of the increase in the 53 children whose growth was delayed before starting treatment. Among the 18 children whose growth was normal or accelerated before treatment, growth velocity increased, but not significantly, during treatment. Over the 4 years, there were no significant differences in the total steroid dose among those with delayed growth and those with normal growth.

After 24 months of treatment, disease was inactive in 52% of the patients, and activity had decreased in the remainder, Dr. Tynjälä and her colleagues wrote.

The change in inflammatory activity “remained a significant predictor of the growth velocity, even after glucocorticoids were taken into account,” suggesting that the improved growth velocity may be because of the reduction in inflammation and not “a direct effect of biological agents on growth or on skeletal maturation.”

ROCKVILLE, MD. — Need proof that postmarketing risk management programs can work?

From March 1, 2005, through March 17, 2006, the year after the diabetes drug pramlintide became available in the United States, there were 10 reports of medically assisted severe hypoglycemia (MASH) in patients treated with the drug, Dr. Gary L. Bloomgren said at a meeting sponsored by the International Society for Pharmacoepidemiology.

This is a rate of 0.06 events per 1,000 units or vials of pramlintide dispensed, all occurring in type 1 patients within the first month of treatment, which “fits very clearly” with what was observed in the preapproval clinical program, noted Dr. Bloomgren, executive director of global safety, Amylin Pharmaceuticals Inc., San Diego.

The phase II and III controlled trials were blinded and allowed patients to make only minimal changes to their diets, a circumstance that may have contributed to higher rates of insulin-induced hypoglycemia, Dr. Bloomgren said. During the first 3 months of the trials, the incidence of MASH was 3% among those on placebo and insulin vs. about 7% among those on pramlintide and insulin in placebo-controlled studies in which insulin was not reduced.

The cumulative MASH reports during the year after approval were estimated as 3 cases per 1,000 patient-years of use among type 1 diabetics. He compared this with 100 MASH cases per 1,000 patient-years among those on pramlintide and insulin during the first 3 months of use in the open-label clinical practice study (in which the insulin dose was reduced during initiation), and 40 MASH events per 1,000 patient-years over the subsequent 3–6 months of treatment.

Dr. Bloomgren attributed what he described as a “safe start” to the drug's use in the United States to the risk management program in place when it was approved. The plan, which included warnings in the label about the risk of severe hypoglycemia and limited drug promotion to diabetes specialists, is the reason the drug is on the market today, he said.

Pramlintide, which is marketed by Amylin under the trade name Symlin, is a synthetic analogue of human amylin, a naturally occurring neuroendocrine hormone that is secreted with insulin by pancreatic B cells and is also deficient in diabetes. It was approved in March 2005 for use at mealtimes as an adjunct to insulin in patients with type 1 or 2 diabetes who have not achieved their desired glucose control despite optimal insulin therapy.

The risk management program was instituted to manage the risk of severe insulin-induced hypoglycemia, which had been identified as a serious safety issue associated with the drug. Overall, the risk-benefit assessment favored approval, given the glycemic control evidenced by HbA_1c and postprandial glucose values.

MASH is defined as hypoglycemia requiring treatment with a glucagon injection or IV glucose, hospitalization or an emergency department visit, or paramedic assistance. This was distinguished from mild to moderate hypoglycemia and patient-ascertained severe hypoglycemia.

Factors that were identified before approval as increasing the risk of insulin-induced hypoglycemia included being a type 1 diabetic, having had recent episodes of hypoglycemia and/or a history of hypoglycemia unawareness, and not reducing mealtime insulin before starting pramlintide. Carefully selecting candidates for pramlintide was emphasized as “critical” to the safe and effective use of the drug, Dr. Bloomgren said.

ROCKVILLE, MD. — Need proof that postmarketing risk management programs can work?

From March 1, 2005, through March 17, 2006, the year after the diabetes drug pramlintide became available in the United States, there were 10 reports of medically assisted severe hypoglycemia (MASH) in patients treated with the drug, Dr. Gary L. Bloomgren said at a meeting sponsored by the International Society for Pharmacoepidemiology.

This is a rate of 0.06 events per 1,000 units or vials of pramlintide dispensed, all occurring in type 1 patients within the first month of treatment, which “fits very clearly” with what was observed in the preapproval clinical program, noted Dr. Bloomgren, executive director of global safety, Amylin Pharmaceuticals Inc., San Diego.

The phase II and III controlled trials were blinded and allowed patients to make only minimal changes to their diets, a circumstance that may have contributed to higher rates of insulin-induced hypoglycemia, Dr. Bloomgren said. During the first 3 months of the trials, the incidence of MASH was 3% among those on placebo and insulin vs. about 7% among those on pramlintide and insulin in placebo-controlled studies in which insulin was not reduced.

The cumulative MASH reports during the year after approval were estimated as 3 cases per 1,000 patient-years of use among type 1 diabetics. He compared this with 100 MASH cases per 1,000 patient-years among those on pramlintide and insulin during the first 3 months of use in the open-label clinical practice study (in which the insulin dose was reduced during initiation), and 40 MASH events per 1,000 patient-years over the subsequent 3–6 months of treatment.

Dr. Bloomgren attributed what he described as a “safe start” to the drug's use in the United States to the risk management program in place when it was approved. The plan, which included warnings in the label about the risk of severe hypoglycemia and limited drug promotion to diabetes specialists, is the reason the drug is on the market today, he said.

Pramlintide, which is marketed by Amylin under the trade name Symlin, is a synthetic analogue of human amylin, a naturally occurring neuroendocrine hormone that is secreted with insulin by pancreatic B cells and is also deficient in diabetes. It was approved in March 2005 for use at mealtimes as an adjunct to insulin in patients with type 1 or 2 diabetes who have not achieved their desired glucose control despite optimal insulin therapy.

The risk management program was instituted to manage the risk of severe insulin-induced hypoglycemia, which had been identified as a serious safety issue associated with the drug. Overall, the risk-benefit assessment favored approval, given the glycemic control evidenced by HbA_1c and postprandial glucose values.

MASH is defined as hypoglycemia requiring treatment with a glucagon injection or IV glucose, hospitalization or an emergency department visit, or paramedic assistance. This was distinguished from mild to moderate hypoglycemia and patient-ascertained severe hypoglycemia.

Factors that were identified before approval as increasing the risk of insulin-induced hypoglycemia included being a type 1 diabetic, having had recent episodes of hypoglycemia and/or a history of hypoglycemia unawareness, and not reducing mealtime insulin before starting pramlintide. Carefully selecting candidates for pramlintide was emphasized as “critical” to the safe and effective use of the drug, Dr. Bloomgren said.

ROCKVILLE, MD. — Need proof that postmarketing risk management programs can work?

From March 1, 2005, through March 17, 2006, the year after the diabetes drug pramlintide became available in the United States, there were 10 reports of medically assisted severe hypoglycemia (MASH) in patients treated with the drug, Dr. Gary L. Bloomgren said at a meeting sponsored by the International Society for Pharmacoepidemiology.

This is a rate of 0.06 events per 1,000 units or vials of pramlintide dispensed, all occurring in type 1 patients within the first month of treatment, which “fits very clearly” with what was observed in the preapproval clinical program, noted Dr. Bloomgren, executive director of global safety, Amylin Pharmaceuticals Inc., San Diego.

The phase II and III controlled trials were blinded and allowed patients to make only minimal changes to their diets, a circumstance that may have contributed to higher rates of insulin-induced hypoglycemia, Dr. Bloomgren said. During the first 3 months of the trials, the incidence of MASH was 3% among those on placebo and insulin vs. about 7% among those on pramlintide and insulin in placebo-controlled studies in which insulin was not reduced.

The cumulative MASH reports during the year after approval were estimated as 3 cases per 1,000 patient-years of use among type 1 diabetics. He compared this with 100 MASH cases per 1,000 patient-years among those on pramlintide and insulin during the first 3 months of use in the open-label clinical practice study (in which the insulin dose was reduced during initiation), and 40 MASH events per 1,000 patient-years over the subsequent 3–6 months of treatment.

Dr. Bloomgren attributed what he described as a “safe start” to the drug's use in the United States to the risk management program in place when it was approved. The plan, which included warnings in the label about the risk of severe hypoglycemia and limited drug promotion to diabetes specialists, is the reason the drug is on the market today, he said.

Pramlintide, which is marketed by Amylin under the trade name Symlin, is a synthetic analogue of human amylin, a naturally occurring neuroendocrine hormone that is secreted with insulin by pancreatic B cells and is also deficient in diabetes. It was approved in March 2005 for use at mealtimes as an adjunct to insulin in patients with type 1 or 2 diabetes who have not achieved their desired glucose control despite optimal insulin therapy.

The risk management program was instituted to manage the risk of severe insulin-induced hypoglycemia, which had been identified as a serious safety issue associated with the drug. Overall, the risk-benefit assessment favored approval, given the glycemic control evidenced by HbA_1c and postprandial glucose values.

MASH is defined as hypoglycemia requiring treatment with a glucagon injection or IV glucose, hospitalization or an emergency department visit, or paramedic assistance. This was distinguished from mild to moderate hypoglycemia and patient-ascertained severe hypoglycemia.

Factors that were identified before approval as increasing the risk of insulin-induced hypoglycemia included being a type 1 diabetic, having had recent episodes of hypoglycemia and/or a history of hypoglycemia unawareness, and not reducing mealtime insulin before starting pramlintide. Carefully selecting candidates for pramlintide was emphasized as “critical” to the safe and effective use of the drug, Dr. Bloomgren said.

Safety information that has been added to the revised label of natalizumab is highlighted in a “dear healthcare professional” letter and timed to coincide with the reintroduction of the monoclonal antibody in the United States as monotherapy for people with relapsing forms of multiple sclerosis.

The letter, released in July by Biogen Idec and Elan, the companies that market natalizumab as Tysabri, includes a copy of the black box warning about the risk of progressive multifocal leukoencephalopathy (PML) associated with treatment. It also refers to the two cases of PML diagnosed in 1,869 patients with MS who were treated with natalizumab for a median of 120 weeks, and a third case in a patient with Crohn's disease who had received 8 doses, among 1,043 patients with Crohn's who received the treatment.

The warning also includes the recommendation that health care professionals monitor patients on natalizumab for any new sign or symptoms “that may be suggestive of PML,” and that treatment should be immediately stopped at the first sign or symptom suggestive of PML.

Because of this risk, which cannot be precisely estimated, the Food and Drug Administration approved the reintroduction of natalizumab under a restricted distribution program, called the TOUCH Prescribing Program, which requires prescribing physicians, infusion centers, and pharmacies associated with infusion centers to register with the program to prescribe, distribute, or infuse the product.

Natalizumab was approved in November 2004, and withdrawn by the manufacturer in February 2005 after two cases of PML were reported. Earlier this year, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee recommended that natalizumab should become available again, with a stringent risk management program, and that it be limited to patients with relapsing features of the disease, only as monotherapy.

The dear doctor letter is available on the FDA's Medwatch site at www.fda.gov/medwatch/safety/2006/safety06.htm#Tysabriwww.fda.gov/medwatch

Safety information that has been added to the revised label of natalizumab is highlighted in a “dear healthcare professional” letter and timed to coincide with the reintroduction of the monoclonal antibody in the United States as monotherapy for people with relapsing forms of multiple sclerosis.

The letter, released in July by Biogen Idec and Elan, the companies that market natalizumab as Tysabri, includes a copy of the black box warning about the risk of progressive multifocal leukoencephalopathy (PML) associated with treatment. It also refers to the two cases of PML diagnosed in 1,869 patients with MS who were treated with natalizumab for a median of 120 weeks, and a third case in a patient with Crohn's disease who had received 8 doses, among 1,043 patients with Crohn's who received the treatment.

The warning also includes the recommendation that health care professionals monitor patients on natalizumab for any new sign or symptoms “that may be suggestive of PML,” and that treatment should be immediately stopped at the first sign or symptom suggestive of PML.

Because of this risk, which cannot be precisely estimated, the Food and Drug Administration approved the reintroduction of natalizumab under a restricted distribution program, called the TOUCH Prescribing Program, which requires prescribing physicians, infusion centers, and pharmacies associated with infusion centers to register with the program to prescribe, distribute, or infuse the product.

Natalizumab was approved in November 2004, and withdrawn by the manufacturer in February 2005 after two cases of PML were reported. Earlier this year, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee recommended that natalizumab should become available again, with a stringent risk management program, and that it be limited to patients with relapsing features of the disease, only as monotherapy.

The dear doctor letter is available on the FDA's Medwatch site at www.fda.gov/medwatch/safety/2006/safety06.htm#Tysabriwww.fda.gov/medwatch

Safety information that has been added to the revised label of natalizumab is highlighted in a “dear healthcare professional” letter and timed to coincide with the reintroduction of the monoclonal antibody in the United States as monotherapy for people with relapsing forms of multiple sclerosis.

The letter, released in July by Biogen Idec and Elan, the companies that market natalizumab as Tysabri, includes a copy of the black box warning about the risk of progressive multifocal leukoencephalopathy (PML) associated with treatment. It also refers to the two cases of PML diagnosed in 1,869 patients with MS who were treated with natalizumab for a median of 120 weeks, and a third case in a patient with Crohn's disease who had received 8 doses, among 1,043 patients with Crohn's who received the treatment.

The warning also includes the recommendation that health care professionals monitor patients on natalizumab for any new sign or symptoms “that may be suggestive of PML,” and that treatment should be immediately stopped at the first sign or symptom suggestive of PML.

Because of this risk, which cannot be precisely estimated, the Food and Drug Administration approved the reintroduction of natalizumab under a restricted distribution program, called the TOUCH Prescribing Program, which requires prescribing physicians, infusion centers, and pharmacies associated with infusion centers to register with the program to prescribe, distribute, or infuse the product.

Natalizumab was approved in November 2004, and withdrawn by the manufacturer in February 2005 after two cases of PML were reported. Earlier this year, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee recommended that natalizumab should become available again, with a stringent risk management program, and that it be limited to patients with relapsing features of the disease, only as monotherapy.

The dear doctor letter is available on the FDA's Medwatch site at www.fda.gov/medwatch/safety/2006/safety06.htm#Tysabriwww.fda.gov/medwatch

A patient-activated transdermal product for short-term management of acute postoperative pain in adults requiring opioid analgesia has received Food and Drug Administration approval.

The fentanyl iontophoretic transdermal system, marketed under the trade name IONSYS by Alza Corp., was approved for use only in hospitalized patients.

In an interview, Dr. Eugene R. Viscusi, director of regional anesthesia and acute pain management at the medical school of Thomas Jefferson University, Philadelphia, described IONSYS as a compact, preprogrammed, needle-free system that provides an alternative to administering morphine via intravenous patient-controlled analgesia (PCA).

Each unit is about 2 by 3 inches, with adhesive backing and a dosing button. The patient double clicks the button when analgesia is needed, and 40 mcg of fentanyl is delivered over 10 minutes.

The approval of IONSYS and of DepoDur, a sustained-release injectable morphine for epidural use approved in 2004, illustrates the movement of postoperative analgesia “into this realm of less invasive and less burdensome technologies” that are more user-friendly and less cumbersome for patients and nursing staff, noted Dr. Viscusi. He has served as a scientific adviser to Alza, which has provided research support to Thomas Jefferson University.

IONSYS is applied to intact, nonirritated, nonirradiated skin on the chest or upper outer arm, and is replaced every 24 hours or when 80 doses have been administered. A maximum of 6 doses per hour and 80 doses over 24 hours can be administered; no more than 1 dose every 10 minutes can be released. Patients should be titrated to comfort before starting treatment, the label says.

IONSYS was compared with placebo or with IV PCA morphine in seven studies of 3,392 patients (2,114 using IONSYS) aged 18–90 years, with body types ranging from very thin to obese. In those studies, IONSYS provided effective acute pain management after a variety of surgical procedures, including orthopedic, general, and gynecologic surgery, according to Dr. Viscusi. The most common adverse effects among those treated with IONSYS included nausea, vomiting, application site-related erythema, fever, and headache.

Dr. Viscusi was the lead author of a study in which more than 600 postoperative adult patients were randomly assigned to either IONSYS or IV PCA. The patients rated the two approaches “as basically therapeutically equivalent” in terms of pain control after 24 hours of treatment, he said. Opioid-related side effects were comparable in the study (JAMA 2004;291:1333–41).

Other aspects of the transdermal system have not been directly compared with IV PCA, but because IONSYS is compact, self-contained, and needle-free, Dr. Viscusi believes that it should be easier to use, won't impede physical therapy or patient activity, and will reduce the risk of medication errors, compared with IV PCA.

Fentanyl is a schedule II drug with a high potential for abuse.

IONSYS is a compact, preprogrammed, needle-free system that provides an alternative to administering morphine intravenously. Ortho-McNeil, Inc.

A patient-activated transdermal product for short-term management of acute postoperative pain in adults requiring opioid analgesia has received Food and Drug Administration approval.

The fentanyl iontophoretic transdermal system, marketed under the trade name IONSYS by Alza Corp., was approved for use only in hospitalized patients.

In an interview, Dr. Eugene R. Viscusi, director of regional anesthesia and acute pain management at the medical school of Thomas Jefferson University, Philadelphia, described IONSYS as a compact, preprogrammed, needle-free system that provides an alternative to administering morphine via intravenous patient-controlled analgesia (PCA).

Each unit is about 2 by 3 inches, with adhesive backing and a dosing button. The patient double clicks the button when analgesia is needed, and 40 mcg of fentanyl is delivered over 10 minutes.

The approval of IONSYS and of DepoDur, a sustained-release injectable morphine for epidural use approved in 2004, illustrates the movement of postoperative analgesia “into this realm of less invasive and less burdensome technologies” that are more user-friendly and less cumbersome for patients and nursing staff, noted Dr. Viscusi. He has served as a scientific adviser to Alza, which has provided research support to Thomas Jefferson University.

IONSYS is applied to intact, nonirritated, nonirradiated skin on the chest or upper outer arm, and is replaced every 24 hours or when 80 doses have been administered. A maximum of 6 doses per hour and 80 doses over 24 hours can be administered; no more than 1 dose every 10 minutes can be released. Patients should be titrated to comfort before starting treatment, the label says.

IONSYS was compared with placebo or with IV PCA morphine in seven studies of 3,392 patients (2,114 using IONSYS) aged 18–90 years, with body types ranging from very thin to obese. In those studies, IONSYS provided effective acute pain management after a variety of surgical procedures, including orthopedic, general, and gynecologic surgery, according to Dr. Viscusi. The most common adverse effects among those treated with IONSYS included nausea, vomiting, application site-related erythema, fever, and headache.

Dr. Viscusi was the lead author of a study in which more than 600 postoperative adult patients were randomly assigned to either IONSYS or IV PCA. The patients rated the two approaches “as basically therapeutically equivalent” in terms of pain control after 24 hours of treatment, he said. Opioid-related side effects were comparable in the study (JAMA 2004;291:1333–41).

Other aspects of the transdermal system have not been directly compared with IV PCA, but because IONSYS is compact, self-contained, and needle-free, Dr. Viscusi believes that it should be easier to use, won't impede physical therapy or patient activity, and will reduce the risk of medication errors, compared with IV PCA.

Fentanyl is a schedule II drug with a high potential for abuse.

IONSYS is a compact, preprogrammed, needle-free system that provides an alternative to administering morphine intravenously. Ortho-McNeil, Inc.

A patient-activated transdermal product for short-term management of acute postoperative pain in adults requiring opioid analgesia has received Food and Drug Administration approval.

The fentanyl iontophoretic transdermal system, marketed under the trade name IONSYS by Alza Corp., was approved for use only in hospitalized patients.

In an interview, Dr. Eugene R. Viscusi, director of regional anesthesia and acute pain management at the medical school of Thomas Jefferson University, Philadelphia, described IONSYS as a compact, preprogrammed, needle-free system that provides an alternative to administering morphine via intravenous patient-controlled analgesia (PCA).

Each unit is about 2 by 3 inches, with adhesive backing and a dosing button. The patient double clicks the button when analgesia is needed, and 40 mcg of fentanyl is delivered over 10 minutes.

The approval of IONSYS and of DepoDur, a sustained-release injectable morphine for epidural use approved in 2004, illustrates the movement of postoperative analgesia “into this realm of less invasive and less burdensome technologies” that are more user-friendly and less cumbersome for patients and nursing staff, noted Dr. Viscusi. He has served as a scientific adviser to Alza, which has provided research support to Thomas Jefferson University.

IONSYS is applied to intact, nonirritated, nonirradiated skin on the chest or upper outer arm, and is replaced every 24 hours or when 80 doses have been administered. A maximum of 6 doses per hour and 80 doses over 24 hours can be administered; no more than 1 dose every 10 minutes can be released. Patients should be titrated to comfort before starting treatment, the label says.

IONSYS was compared with placebo or with IV PCA morphine in seven studies of 3,392 patients (2,114 using IONSYS) aged 18–90 years, with body types ranging from very thin to obese. In those studies, IONSYS provided effective acute pain management after a variety of surgical procedures, including orthopedic, general, and gynecologic surgery, according to Dr. Viscusi. The most common adverse effects among those treated with IONSYS included nausea, vomiting, application site-related erythema, fever, and headache.

Dr. Viscusi was the lead author of a study in which more than 600 postoperative adult patients were randomly assigned to either IONSYS or IV PCA. The patients rated the two approaches “as basically therapeutically equivalent” in terms of pain control after 24 hours of treatment, he said. Opioid-related side effects were comparable in the study (JAMA 2004;291:1333–41).

Other aspects of the transdermal system have not been directly compared with IV PCA, but because IONSYS is compact, self-contained, and needle-free, Dr. Viscusi believes that it should be easier to use, won't impede physical therapy or patient activity, and will reduce the risk of medication errors, compared with IV PCA.

Fentanyl is a schedule II drug with a high potential for abuse.

IONSYS is a compact, preprogrammed, needle-free system that provides an alternative to administering morphine intravenously. Ortho-McNeil, Inc.