Elizabeth Mechcatie

SILVER SPRING, MD. – With their increasing prevalence, drug shortages in the United States have led to delays in treatment, forced the use of less effective alternatives, and encouraged a burgeoning gray market that sells tough-to-obtain medications at highly inflated prices, according to stakeholders gathered at a recent Food and Drug Administration meeting.

Shortfalls in drug supply have increased in the United States, with 178 shortages of products reported in 2010, up from 61 in 2005, according to Dr. Edward Cox, coordinator of the FDA’s drug shortage program. Disproportionately affected are generic drugs and sterile injectable products; the latter accounted for two-thirds of the shortages last year. About half of the injectable shortages were caused by problems with product quality, followed by manufacturing delays (21%) and discontinuations (11%), and other issues including an increase in demand created by another shortage, he said at the meeting.

As with older generic drugs, there’s little financial incentive to produce older sterile injectables, which sell for as little as 48 cents for a 20-mL vial of propofol. In such cases, manufacturing glitches can often convince companies to pull the plug on a product, creating shortages.

Most hospitals aren’t immune. A June 2011 survey of 820 nonfederal, short-term, acute care hospitals by the American Hospital Association found that almost 99% had experienced one or more drugs shortages in the first 6 months of 2011; 44% reported at least 21 shortages during that time. In addition, nearly half reported experiencing drug shortages on a daily basis, 40% on a weekly basis, and 13% on a monthly basis.

Almost all these hospitals (96%) had experienced shortages of anesthesia for surgery, followed by drugs used for emergency care (91%), cardiovascular care (90%), GI/nutrition (89%), pain management (88%), infectious disease (83%), and oncology (66%).

Drug shortages have hit the fields of oncology and anesthesiology particularly hard, often causing the delay or postponement of clinical trials of cancer treatments.

Shortages of propofol and succinylcholine have been common. Dr. Frederick Blum, past president of the American College of Emergency Physicians, who practices in Morgantown, West Virginia, described being told there was no succinylcholine available when he recently requested it as he was about to intubate a trauma patient. When he asked for the next best drug, it wasn’t available either because supply had been depleted from the succinylcholine shortage. A third, less-than-ideal alternative was found. But Dr. Blum said that after 30 years of practice, during which time he probably has used succinylcholine thousands of times, he left that shift shaking his head about the need to resort to using a third-choice drug.

Before the shortage of succinylcholine was resolved earlier this year, shortages of the agent also resulted in postponed surgeries at Veterans Administration Medical Centers.

Generic Cancer Drugs Drying Up

Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society, noted that many generic cancer drugs are in short supply. Such drugs, developed years ago, often are inexpensive and "remain mainstays of many currently available and effective cancer treatment programs," he said.

Generic cancer drugs that are in short supply include fluorouracil (5-FU), paclitaxel, daunorubicin, cytarabine, bleomycin, and cisplatin.

In many cases, such shortages are causing patients to have to travel further to get the drugs they need. Alternatively, they are treated with second- and third-line therapies that are not necessarily as effective, Dr. Lichtenfeld said. Many adult and pediatric trials of cancer treatments have been suspended when supply of the active control drug is no longer available, he added, and ACS is regularly contacted by patients and families who are looking for medications in short supply.

Exacerbating a shortage situation is the emergence of gray markets that trigger hoarding, he said.

Dr. Laura Porter of the Colon Cancer Alliance said that there have been shortages of 5 of 22 drugs used to treat for colon cancer, including 5-FU and leucovorin. Of the five, four are generic drugs. Last year, there were eight manufacturers of irinotecan, another drug used to treat colon cancer; today, there are only two, and the FDA has asked another company to start manufacturing the colon cancer agent.

At St. Jude Children’s Research Hospital, Memphis, 1-4 drug shortages were reported every month in 2009, but in 2011, an average of 22 shortages have been reported every month, peaking at 28 in July. Notable shortages over the past year have included every component of total parenteral nutrition (TPN) and multivitamin injections, with the latter resulting in a hospitalization of a patient who could not take oral multivitamins and developed neurotoxicity and a thiamine deficiency, said James Hoffman, Pharm. D., the hospital’s medication outcomes and safety officer.

Shortages of chemotherapy drugs have increased over the past 2 years. At St. Jude, where 85% of the cancer patients are enrolled in clinical trials, enrollment in acute myeloid leukemia protocols were suspended because of a shortage of cytarabine and lymphoma protocols were modified because of the shortage of mechlorethamine (nitrogen mustard). He pointed out that with 10 drugs, about 90% of patients with childhood acute lymphoblastic leukemia, the most common childhood cancer, can be cured, but over the last decade, 8 of these 10 drugs have been temporarily unavailable.

Substitute drugs can often be more expensive and involve additional labor costs, adding up to an estimated $415 million annually, according to Bryant Mangum, vice president of pharmacy services at Premier Healthcare Alliance, a network of over 2,500 hospitals in the United States. An analysis of 636 unsolicited sales offers from gray-market vendors conducted by Premier found that the average markup of a drug price was 650%. Almost half the drugs were marked up by at least 1,000%, more than 25% were marked up by at least 2,000% – and a drug used to treat hypertension that usually costs $25.90 was being offered at $1,200, "a staggering increase," he said at the meeting.

The greatest markups were for drugs used to treat patients in the areas of critical care sedation and surgery, chemotherapy, emergency care, and anti-infective drugs, he said.

How the FDA Handles Shortages

Currently, the FDA’s approach to drug shortages involves encouraging companies that make a product that is in short supply to ramp up manufacturing. The FDA also works with firms to address problems behind the shortage, such as manufacturing or quality issues. In rare cases, the FDA allows a product from an unapproved source to be imported into the U.S. temporarily, which was the case in 2010 for propofol and in 2011 for foscarnet, norepinephrine, leucovorin, and capecitabine.

Manufacturers have been giving the agency earlier notification about the potential for supply issues, a strategy that the FDA claims has successfully head off some shortages. Such reports have helped prevent 99 shortages so far this year, an increase from 38 in 2010, Dr. Cox said at the meeting. Most of the prevented shortages (84) were derailed by expediting FDA review of new manufacturing sites, suppliers and other issues that affect the drug production.

Other recommendations for resolving, preventing, and alleviating drug shortages now and in the future include creating stockpiles of certain drugs, similar to vaccine stockpiles; developing guidelines on treatment alternatives when there is a shortage of a drug, such as an antibiotic; and improving communications about drug shortages between FDA and stakeholders.

Clinicians need to be notified faster about shortages so they can be better prepared, according to several practicing physicians who spoke at the meeting. Of the hospitals surveyed by the AHA, 70% responded that the available information on how to manage drug shortages was not adequate. Sources for such information include the American Society of Health-System Pharmacists, the FDA drug shortage website, and direct communication with manufacturers.

Dr. Blum, Dr. Cox, and Mr. Mangum had no disclosures. Dr. Lichtenfeld disclosed that he owns Johnson & Johnson stock and that the ACS receives grants from pharmaceutical companies and the foundations they oversee. Disclosure statements for Mr. Hoffman and Dr. Porter were not available.

To report drug shortages, call 888-463-6332, e-mail drug shortages, or go to the FDA drug shortage website. To report shortages of biologic products (such as blood, vaccines, or allergenics), call 301-827-4239 or e-mail CBER shortages.

SILVER SPRING, MD. – With their increasing prevalence, drug shortages in the United States have led to delays in treatment, forced the use of less effective alternatives, and encouraged a burgeoning gray market that sells tough-to-obtain medications at highly inflated prices, according to stakeholders gathered at a recent Food and Drug Administration meeting.

Shortfalls in drug supply have increased in the United States, with 178 shortages of products reported in 2010, up from 61 in 2005, according to Dr. Edward Cox, coordinator of the FDA’s drug shortage program. Disproportionately affected are generic drugs and sterile injectable products; the latter accounted for two-thirds of the shortages last year. About half of the injectable shortages were caused by problems with product quality, followed by manufacturing delays (21%) and discontinuations (11%), and other issues including an increase in demand created by another shortage, he said at the meeting.

As with older generic drugs, there’s little financial incentive to produce older sterile injectables, which sell for as little as 48 cents for a 20-mL vial of propofol. In such cases, manufacturing glitches can often convince companies to pull the plug on a product, creating shortages.

Most hospitals aren’t immune. A June 2011 survey of 820 nonfederal, short-term, acute care hospitals by the American Hospital Association found that almost 99% had experienced one or more drugs shortages in the first 6 months of 2011; 44% reported at least 21 shortages during that time. In addition, nearly half reported experiencing drug shortages on a daily basis, 40% on a weekly basis, and 13% on a monthly basis.

Almost all these hospitals (96%) had experienced shortages of anesthesia for surgery, followed by drugs used for emergency care (91%), cardiovascular care (90%), GI/nutrition (89%), pain management (88%), infectious disease (83%), and oncology (66%).

Drug shortages have hit the fields of oncology and anesthesiology particularly hard, often causing the delay or postponement of clinical trials of cancer treatments.

Shortages of propofol and succinylcholine have been common. Dr. Frederick Blum, past president of the American College of Emergency Physicians, who practices in Morgantown, West Virginia, described being told there was no succinylcholine available when he recently requested it as he was about to intubate a trauma patient. When he asked for the next best drug, it wasn’t available either because supply had been depleted from the succinylcholine shortage. A third, less-than-ideal alternative was found. But Dr. Blum said that after 30 years of practice, during which time he probably has used succinylcholine thousands of times, he left that shift shaking his head about the need to resort to using a third-choice drug.

Before the shortage of succinylcholine was resolved earlier this year, shortages of the agent also resulted in postponed surgeries at Veterans Administration Medical Centers.

Generic Cancer Drugs Drying Up

Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society, noted that many generic cancer drugs are in short supply. Such drugs, developed years ago, often are inexpensive and "remain mainstays of many currently available and effective cancer treatment programs," he said.

Generic cancer drugs that are in short supply include fluorouracil (5-FU), paclitaxel, daunorubicin, cytarabine, bleomycin, and cisplatin.

In many cases, such shortages are causing patients to have to travel further to get the drugs they need. Alternatively, they are treated with second- and third-line therapies that are not necessarily as effective, Dr. Lichtenfeld said. Many adult and pediatric trials of cancer treatments have been suspended when supply of the active control drug is no longer available, he added, and ACS is regularly contacted by patients and families who are looking for medications in short supply.

Exacerbating a shortage situation is the emergence of gray markets that trigger hoarding, he said.

Dr. Laura Porter of the Colon Cancer Alliance said that there have been shortages of 5 of 22 drugs used to treat for colon cancer, including 5-FU and leucovorin. Of the five, four are generic drugs. Last year, there were eight manufacturers of irinotecan, another drug used to treat colon cancer; today, there are only two, and the FDA has asked another company to start manufacturing the colon cancer agent.

At St. Jude Children’s Research Hospital, Memphis, 1-4 drug shortages were reported every month in 2009, but in 2011, an average of 22 shortages have been reported every month, peaking at 28 in July. Notable shortages over the past year have included every component of total parenteral nutrition (TPN) and multivitamin injections, with the latter resulting in a hospitalization of a patient who could not take oral multivitamins and developed neurotoxicity and a thiamine deficiency, said James Hoffman, Pharm. D., the hospital’s medication outcomes and safety officer.

Shortages of chemotherapy drugs have increased over the past 2 years. At St. Jude, where 85% of the cancer patients are enrolled in clinical trials, enrollment in acute myeloid leukemia protocols were suspended because of a shortage of cytarabine and lymphoma protocols were modified because of the shortage of mechlorethamine (nitrogen mustard). He pointed out that with 10 drugs, about 90% of patients with childhood acute lymphoblastic leukemia, the most common childhood cancer, can be cured, but over the last decade, 8 of these 10 drugs have been temporarily unavailable.

Substitute drugs can often be more expensive and involve additional labor costs, adding up to an estimated $415 million annually, according to Bryant Mangum, vice president of pharmacy services at Premier Healthcare Alliance, a network of over 2,500 hospitals in the United States. An analysis of 636 unsolicited sales offers from gray-market vendors conducted by Premier found that the average markup of a drug price was 650%. Almost half the drugs were marked up by at least 1,000%, more than 25% were marked up by at least 2,000% – and a drug used to treat hypertension that usually costs $25.90 was being offered at $1,200, "a staggering increase," he said at the meeting.

The greatest markups were for drugs used to treat patients in the areas of critical care sedation and surgery, chemotherapy, emergency care, and anti-infective drugs, he said.

How the FDA Handles Shortages

Currently, the FDA’s approach to drug shortages involves encouraging companies that make a product that is in short supply to ramp up manufacturing. The FDA also works with firms to address problems behind the shortage, such as manufacturing or quality issues. In rare cases, the FDA allows a product from an unapproved source to be imported into the U.S. temporarily, which was the case in 2010 for propofol and in 2011 for foscarnet, norepinephrine, leucovorin, and capecitabine.

Manufacturers have been giving the agency earlier notification about the potential for supply issues, a strategy that the FDA claims has successfully head off some shortages. Such reports have helped prevent 99 shortages so far this year, an increase from 38 in 2010, Dr. Cox said at the meeting. Most of the prevented shortages (84) were derailed by expediting FDA review of new manufacturing sites, suppliers and other issues that affect the drug production.

Other recommendations for resolving, preventing, and alleviating drug shortages now and in the future include creating stockpiles of certain drugs, similar to vaccine stockpiles; developing guidelines on treatment alternatives when there is a shortage of a drug, such as an antibiotic; and improving communications about drug shortages between FDA and stakeholders.

Clinicians need to be notified faster about shortages so they can be better prepared, according to several practicing physicians who spoke at the meeting. Of the hospitals surveyed by the AHA, 70% responded that the available information on how to manage drug shortages was not adequate. Sources for such information include the American Society of Health-System Pharmacists, the FDA drug shortage website, and direct communication with manufacturers.

Dr. Blum, Dr. Cox, and Mr. Mangum had no disclosures. Dr. Lichtenfeld disclosed that he owns Johnson & Johnson stock and that the ACS receives grants from pharmaceutical companies and the foundations they oversee. Disclosure statements for Mr. Hoffman and Dr. Porter were not available.

To report drug shortages, call 888-463-6332, e-mail drug shortages, or go to the FDA drug shortage website. To report shortages of biologic products (such as blood, vaccines, or allergenics), call 301-827-4239 or e-mail CBER shortages.

SILVER SPRING, MD. – With their increasing prevalence, drug shortages in the United States have led to delays in treatment, forced the use of less effective alternatives, and encouraged a burgeoning gray market that sells tough-to-obtain medications at highly inflated prices, according to stakeholders gathered at a recent Food and Drug Administration meeting.

Shortfalls in drug supply have increased in the United States, with 178 shortages of products reported in 2010, up from 61 in 2005, according to Dr. Edward Cox, coordinator of the FDA’s drug shortage program. Disproportionately affected are generic drugs and sterile injectable products; the latter accounted for two-thirds of the shortages last year. About half of the injectable shortages were caused by problems with product quality, followed by manufacturing delays (21%) and discontinuations (11%), and other issues including an increase in demand created by another shortage, he said at the meeting.

As with older generic drugs, there’s little financial incentive to produce older sterile injectables, which sell for as little as 48 cents for a 20-mL vial of propofol. In such cases, manufacturing glitches can often convince companies to pull the plug on a product, creating shortages.

Most hospitals aren’t immune. A June 2011 survey of 820 nonfederal, short-term, acute care hospitals by the American Hospital Association found that almost 99% had experienced one or more drugs shortages in the first 6 months of 2011; 44% reported at least 21 shortages during that time. In addition, nearly half reported experiencing drug shortages on a daily basis, 40% on a weekly basis, and 13% on a monthly basis.

Almost all these hospitals (96%) had experienced shortages of anesthesia for surgery, followed by drugs used for emergency care (91%), cardiovascular care (90%), GI/nutrition (89%), pain management (88%), infectious disease (83%), and oncology (66%).

Drug shortages have hit the fields of oncology and anesthesiology particularly hard, often causing the delay or postponement of clinical trials of cancer treatments.

Shortages of propofol and succinylcholine have been common. Dr. Frederick Blum, past president of the American College of Emergency Physicians, who practices in Morgantown, West Virginia, described being told there was no succinylcholine available when he recently requested it as he was about to intubate a trauma patient. When he asked for the next best drug, it wasn’t available either because supply had been depleted from the succinylcholine shortage. A third, less-than-ideal alternative was found. But Dr. Blum said that after 30 years of practice, during which time he probably has used succinylcholine thousands of times, he left that shift shaking his head about the need to resort to using a third-choice drug.

Before the shortage of succinylcholine was resolved earlier this year, shortages of the agent also resulted in postponed surgeries at Veterans Administration Medical Centers.

Generic Cancer Drugs Drying Up

Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society, noted that many generic cancer drugs are in short supply. Such drugs, developed years ago, often are inexpensive and "remain mainstays of many currently available and effective cancer treatment programs," he said.

Generic cancer drugs that are in short supply include fluorouracil (5-FU), paclitaxel, daunorubicin, cytarabine, bleomycin, and cisplatin.

In many cases, such shortages are causing patients to have to travel further to get the drugs they need. Alternatively, they are treated with second- and third-line therapies that are not necessarily as effective, Dr. Lichtenfeld said. Many adult and pediatric trials of cancer treatments have been suspended when supply of the active control drug is no longer available, he added, and ACS is regularly contacted by patients and families who are looking for medications in short supply.

Exacerbating a shortage situation is the emergence of gray markets that trigger hoarding, he said.

Dr. Laura Porter of the Colon Cancer Alliance said that there have been shortages of 5 of 22 drugs used to treat for colon cancer, including 5-FU and leucovorin. Of the five, four are generic drugs. Last year, there were eight manufacturers of irinotecan, another drug used to treat colon cancer; today, there are only two, and the FDA has asked another company to start manufacturing the colon cancer agent.

At St. Jude Children’s Research Hospital, Memphis, 1-4 drug shortages were reported every month in 2009, but in 2011, an average of 22 shortages have been reported every month, peaking at 28 in July. Notable shortages over the past year have included every component of total parenteral nutrition (TPN) and multivitamin injections, with the latter resulting in a hospitalization of a patient who could not take oral multivitamins and developed neurotoxicity and a thiamine deficiency, said James Hoffman, Pharm. D., the hospital’s medication outcomes and safety officer.

Shortages of chemotherapy drugs have increased over the past 2 years. At St. Jude, where 85% of the cancer patients are enrolled in clinical trials, enrollment in acute myeloid leukemia protocols were suspended because of a shortage of cytarabine and lymphoma protocols were modified because of the shortage of mechlorethamine (nitrogen mustard). He pointed out that with 10 drugs, about 90% of patients with childhood acute lymphoblastic leukemia, the most common childhood cancer, can be cured, but over the last decade, 8 of these 10 drugs have been temporarily unavailable.

Substitute drugs can often be more expensive and involve additional labor costs, adding up to an estimated $415 million annually, according to Bryant Mangum, vice president of pharmacy services at Premier Healthcare Alliance, a network of over 2,500 hospitals in the United States. An analysis of 636 unsolicited sales offers from gray-market vendors conducted by Premier found that the average markup of a drug price was 650%. Almost half the drugs were marked up by at least 1,000%, more than 25% were marked up by at least 2,000% – and a drug used to treat hypertension that usually costs $25.90 was being offered at $1,200, "a staggering increase," he said at the meeting.

The greatest markups were for drugs used to treat patients in the areas of critical care sedation and surgery, chemotherapy, emergency care, and anti-infective drugs, he said.

How the FDA Handles Shortages

Currently, the FDA’s approach to drug shortages involves encouraging companies that make a product that is in short supply to ramp up manufacturing. The FDA also works with firms to address problems behind the shortage, such as manufacturing or quality issues. In rare cases, the FDA allows a product from an unapproved source to be imported into the U.S. temporarily, which was the case in 2010 for propofol and in 2011 for foscarnet, norepinephrine, leucovorin, and capecitabine.

Manufacturers have been giving the agency earlier notification about the potential for supply issues, a strategy that the FDA claims has successfully head off some shortages. Such reports have helped prevent 99 shortages so far this year, an increase from 38 in 2010, Dr. Cox said at the meeting. Most of the prevented shortages (84) were derailed by expediting FDA review of new manufacturing sites, suppliers and other issues that affect the drug production.

Other recommendations for resolving, preventing, and alleviating drug shortages now and in the future include creating stockpiles of certain drugs, similar to vaccine stockpiles; developing guidelines on treatment alternatives when there is a shortage of a drug, such as an antibiotic; and improving communications about drug shortages between FDA and stakeholders.

Clinicians need to be notified faster about shortages so they can be better prepared, according to several practicing physicians who spoke at the meeting. Of the hospitals surveyed by the AHA, 70% responded that the available information on how to manage drug shortages was not adequate. Sources for such information include the American Society of Health-System Pharmacists, the FDA drug shortage website, and direct communication with manufacturers.

Dr. Blum, Dr. Cox, and Mr. Mangum had no disclosures. Dr. Lichtenfeld disclosed that he owns Johnson & Johnson stock and that the ACS receives grants from pharmaceutical companies and the foundations they oversee. Disclosure statements for Mr. Hoffman and Dr. Porter were not available.

To report drug shortages, call 888-463-6332, e-mail drug shortages, or go to the FDA drug shortage website. To report shortages of biologic products (such as blood, vaccines, or allergenics), call 301-827-4239 or e-mail CBER shortages.

GAITHERSBURG, MD. – A Food and Drug Administration Advisory panel on Oct. 27 did not support the approval of a catheter-based radiofrequency ablation device for treating persistent atrial fibrillation, citing concerns over safety issues.

At the meeting, the FDA’s Circulatory System Devices Panel voted 8 to 2 that the data on the Medtronic cardiac ablation system did not demonstrate that the benefits outweighed the risks of the device for the proposed indication: the treatment of symptomatic, drug refractory, persistent atrial fibrillation (AF) or long-standing persistent AF of up to 4 years in duration. Panelists described it as a pioneering and innovative device that was effective in a difficult-to-treat population and unanimously voted that there was "reasonable assurance" that it was effective for the proposed indication.

But they voted 9 to 1 that there was not reasonable assurance that it was safe, primarily because of the increased rate of strokes around the time of the procedure (3% compared to none among those treated medically in the medical treatment arm of the pivotal study) and the 4% rate of pulmonary vein stenosis and symptomatic narrowing of the pulmonary vein 6 months after treatment with the device (4%).

Panelists were also concerned about reports in the literature of asymptomatic cerebrovascular emboli in patients treated with the device, which has been available in Europe since 2006, where it is approved for the treatment of paroxysmal atrial fibrillation. (Patients in the pivotal trial were not evaluated for asymptomatic cerebrovascular emoboli.)

The components of the catheter-based device include an RF ablation generator and three cardiac ablation catheters, a unique feature for this kind of device. The pulmonary vein ablation catheter is designed to create lesions in the left atrium, the "Multi-Array Septal Catheter" is designed to create lesions on the septal wall of the left atrium, and "Multi-Array Ablation Catheter" is designed to create lesions in the left and/or right atrium.

In the pivotal study, a prospective multicenter study of 210 patients with a history of symptomatic, refractory AF who had failed at least one class I or III anti-arrhythmic drug, patients were randomized to treatment with the device or medical treatment, in a 2:1 ratio. Their mean age was about 60 years and most were men, and had had AF for 4 months to 6 years. The exclusion criteria included having received prior ablation for AF, structural heart disease, NYHA class III or IV, LVEF under 40%, and a history of stroke or TIA.

The primary end point of the study – acute procedural success and at least a 90% reduction in clinically significant AF/atrial flutter on 48-hour Holter at 6 months – was met by 56% of those treated with the device, compared with 26% of those who were medically managed, a statistically significant difference.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

GAITHERSBURG, MD. – A Food and Drug Administration Advisory panel on Oct. 27 did not support the approval of a catheter-based radiofrequency ablation device for treating persistent atrial fibrillation, citing concerns over safety issues.

At the meeting, the FDA’s Circulatory System Devices Panel voted 8 to 2 that the data on the Medtronic cardiac ablation system did not demonstrate that the benefits outweighed the risks of the device for the proposed indication: the treatment of symptomatic, drug refractory, persistent atrial fibrillation (AF) or long-standing persistent AF of up to 4 years in duration. Panelists described it as a pioneering and innovative device that was effective in a difficult-to-treat population and unanimously voted that there was "reasonable assurance" that it was effective for the proposed indication.

But they voted 9 to 1 that there was not reasonable assurance that it was safe, primarily because of the increased rate of strokes around the time of the procedure (3% compared to none among those treated medically in the medical treatment arm of the pivotal study) and the 4% rate of pulmonary vein stenosis and symptomatic narrowing of the pulmonary vein 6 months after treatment with the device (4%).

Panelists were also concerned about reports in the literature of asymptomatic cerebrovascular emboli in patients treated with the device, which has been available in Europe since 2006, where it is approved for the treatment of paroxysmal atrial fibrillation. (Patients in the pivotal trial were not evaluated for asymptomatic cerebrovascular emoboli.)

The components of the catheter-based device include an RF ablation generator and three cardiac ablation catheters, a unique feature for this kind of device. The pulmonary vein ablation catheter is designed to create lesions in the left atrium, the "Multi-Array Septal Catheter" is designed to create lesions on the septal wall of the left atrium, and "Multi-Array Ablation Catheter" is designed to create lesions in the left and/or right atrium.

In the pivotal study, a prospective multicenter study of 210 patients with a history of symptomatic, refractory AF who had failed at least one class I or III anti-arrhythmic drug, patients were randomized to treatment with the device or medical treatment, in a 2:1 ratio. Their mean age was about 60 years and most were men, and had had AF for 4 months to 6 years. The exclusion criteria included having received prior ablation for AF, structural heart disease, NYHA class III or IV, LVEF under 40%, and a history of stroke or TIA.

The primary end point of the study – acute procedural success and at least a 90% reduction in clinically significant AF/atrial flutter on 48-hour Holter at 6 months – was met by 56% of those treated with the device, compared with 26% of those who were medically managed, a statistically significant difference.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

GAITHERSBURG, MD. – A Food and Drug Administration Advisory panel on Oct. 27 did not support the approval of a catheter-based radiofrequency ablation device for treating persistent atrial fibrillation, citing concerns over safety issues.

At the meeting, the FDA’s Circulatory System Devices Panel voted 8 to 2 that the data on the Medtronic cardiac ablation system did not demonstrate that the benefits outweighed the risks of the device for the proposed indication: the treatment of symptomatic, drug refractory, persistent atrial fibrillation (AF) or long-standing persistent AF of up to 4 years in duration. Panelists described it as a pioneering and innovative device that was effective in a difficult-to-treat population and unanimously voted that there was "reasonable assurance" that it was effective for the proposed indication.

But they voted 9 to 1 that there was not reasonable assurance that it was safe, primarily because of the increased rate of strokes around the time of the procedure (3% compared to none among those treated medically in the medical treatment arm of the pivotal study) and the 4% rate of pulmonary vein stenosis and symptomatic narrowing of the pulmonary vein 6 months after treatment with the device (4%).

Panelists were also concerned about reports in the literature of asymptomatic cerebrovascular emboli in patients treated with the device, which has been available in Europe since 2006, where it is approved for the treatment of paroxysmal atrial fibrillation. (Patients in the pivotal trial were not evaluated for asymptomatic cerebrovascular emoboli.)

The components of the catheter-based device include an RF ablation generator and three cardiac ablation catheters, a unique feature for this kind of device. The pulmonary vein ablation catheter is designed to create lesions in the left atrium, the "Multi-Array Septal Catheter" is designed to create lesions on the septal wall of the left atrium, and "Multi-Array Ablation Catheter" is designed to create lesions in the left and/or right atrium.

In the pivotal study, a prospective multicenter study of 210 patients with a history of symptomatic, refractory AF who had failed at least one class I or III anti-arrhythmic drug, patients were randomized to treatment with the device or medical treatment, in a 2:1 ratio. Their mean age was about 60 years and most were men, and had had AF for 4 months to 6 years. The exclusion criteria included having received prior ablation for AF, structural heart disease, NYHA class III or IV, LVEF under 40%, and a history of stroke or TIA.

The primary end point of the study – acute procedural success and at least a 90% reduction in clinically significant AF/atrial flutter on 48-hour Holter at 6 months – was met by 56% of those treated with the device, compared with 26% of those who were medically managed, a statistically significant difference.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel on Oct. 17 unanimously agreed that there was not enough evidence to support approval of rasagiline for slowing the clinical progression of Parkinson’s disease.

The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted 17-0 that the manufacturer of rasagiline, an MAO-B inhibitor, had not provided substantial evidence that the drug was effective in delaying clinical progression of the disease in patients. Rasagiline was approved in 2006 in the United States for the symptomatic treatment of Parkinson’s disease, as initial monotherapy and as adjunct therapy to levodopa; it is marketed as Azilect by Teva Pharmaceuticals Ltd.

The company conducted a study to evaluate the drug’s effects on clinical progression in about 1,100 patients with early, mild Parkinson’s, who were not on other medications for the disease. The patients (mean age 62 years) were enrolled a mean of 138 days after diagnosis and were treated with 1 mg or 2 mg of rasagiline a day or placebo for 36 weeks, at which point those on placebo were switched to 1 mg or 2 mg doses. Progression of disease was measured with the Unified Parkinson Disease Rating Scale (UPDRS).

At 72 weeks, the increase in mean UPDRS scores from baseline was smaller among patients who had been treated with the 1-mg dose from the start of the study than it was in those who had started the 1-mg dose at 36 weeks, indicating less disease progression in the former. The difference was statistically significant.

However, there was no difference in the UPDRS scores from baseline to the end of the study among those who had started the 2-mg dose at the start of the study and those who started the 2-mg dose at 36 weeks.

The FDA reviewer said that the failure of the 2-mg dose to show an effect was "troubling," and added that the results for either dose were not robust.

The panel agreed, cited other issues with the data, and voted unanimously that the study did not provide compelling evidence that the 1-mg once-daily dose was effective. While they agreed that there was an unmet need for a treatment that slowed progression and that the data were promising, they said the evidence did not meet the high bar that should be set for proving such an effect, considering the enormous public health implications of a neuroprotection claim for a Parkinson’s disease treatment.

Currently, no treatment for Parkinson’s – or any other neurologic disorder – is approved for slowing the clinical progression of the disease.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel on Oct. 17 unanimously agreed that there was not enough evidence to support approval of rasagiline for slowing the clinical progression of Parkinson’s disease.

The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted 17-0 that the manufacturer of rasagiline, an MAO-B inhibitor, had not provided substantial evidence that the drug was effective in delaying clinical progression of the disease in patients. Rasagiline was approved in 2006 in the United States for the symptomatic treatment of Parkinson’s disease, as initial monotherapy and as adjunct therapy to levodopa; it is marketed as Azilect by Teva Pharmaceuticals Ltd.

The company conducted a study to evaluate the drug’s effects on clinical progression in about 1,100 patients with early, mild Parkinson’s, who were not on other medications for the disease. The patients (mean age 62 years) were enrolled a mean of 138 days after diagnosis and were treated with 1 mg or 2 mg of rasagiline a day or placebo for 36 weeks, at which point those on placebo were switched to 1 mg or 2 mg doses. Progression of disease was measured with the Unified Parkinson Disease Rating Scale (UPDRS).

At 72 weeks, the increase in mean UPDRS scores from baseline was smaller among patients who had been treated with the 1-mg dose from the start of the study than it was in those who had started the 1-mg dose at 36 weeks, indicating less disease progression in the former. The difference was statistically significant.

However, there was no difference in the UPDRS scores from baseline to the end of the study among those who had started the 2-mg dose at the start of the study and those who started the 2-mg dose at 36 weeks.

The FDA reviewer said that the failure of the 2-mg dose to show an effect was "troubling," and added that the results for either dose were not robust.

The panel agreed, cited other issues with the data, and voted unanimously that the study did not provide compelling evidence that the 1-mg once-daily dose was effective. While they agreed that there was an unmet need for a treatment that slowed progression and that the data were promising, they said the evidence did not meet the high bar that should be set for proving such an effect, considering the enormous public health implications of a neuroprotection claim for a Parkinson’s disease treatment.

Currently, no treatment for Parkinson’s – or any other neurologic disorder – is approved for slowing the clinical progression of the disease.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel on Oct. 17 unanimously agreed that there was not enough evidence to support approval of rasagiline for slowing the clinical progression of Parkinson’s disease.

The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted 17-0 that the manufacturer of rasagiline, an MAO-B inhibitor, had not provided substantial evidence that the drug was effective in delaying clinical progression of the disease in patients. Rasagiline was approved in 2006 in the United States for the symptomatic treatment of Parkinson’s disease, as initial monotherapy and as adjunct therapy to levodopa; it is marketed as Azilect by Teva Pharmaceuticals Ltd.

The company conducted a study to evaluate the drug’s effects on clinical progression in about 1,100 patients with early, mild Parkinson’s, who were not on other medications for the disease. The patients (mean age 62 years) were enrolled a mean of 138 days after diagnosis and were treated with 1 mg or 2 mg of rasagiline a day or placebo for 36 weeks, at which point those on placebo were switched to 1 mg or 2 mg doses. Progression of disease was measured with the Unified Parkinson Disease Rating Scale (UPDRS).

At 72 weeks, the increase in mean UPDRS scores from baseline was smaller among patients who had been treated with the 1-mg dose from the start of the study than it was in those who had started the 1-mg dose at 36 weeks, indicating less disease progression in the former. The difference was statistically significant.

However, there was no difference in the UPDRS scores from baseline to the end of the study among those who had started the 2-mg dose at the start of the study and those who started the 2-mg dose at 36 weeks.

The FDA reviewer said that the failure of the 2-mg dose to show an effect was "troubling," and added that the results for either dose were not robust.

The panel agreed, cited other issues with the data, and voted unanimously that the study did not provide compelling evidence that the 1-mg once-daily dose was effective. While they agreed that there was an unmet need for a treatment that slowed progression and that the data were promising, they said the evidence did not meet the high bar that should be set for proving such an effect, considering the enormous public health implications of a neuroprotection claim for a Parkinson’s disease treatment.

Currently, no treatment for Parkinson’s – or any other neurologic disorder – is approved for slowing the clinical progression of the disease.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel on Oct. 13 voted 11-0 that the benefits of a drug-eluting stent outweighed its risks as a treatment for patients with symptomatic atherosclerotic stenosis of the femoropopliteal arteries.

The FDA’s Circulatory System Devices Panel also unanimously voted that the available data provided "reasonable assurance" that the Zilver PTX drug-eluting stent (DES) was safe and effective for the proposed indication. The panel did not specifically vote on whether to recommend approval.

The Zilver PTX stent is a self-expanding, nitinol stent coated with paclitaxel, which is the active ingredient in the chemotherapy treatment Taxol and in the FDA-approved Taxus coronary stent. Its delivery system is the same as the one used with the Zilver vascular stent, a bare-metal stent (BMS) that is FDA approved for use in iliac arteries.

The Zilver PTX stent’s manufacturer, Cook Medical Inc., has proposed that the Zilver PTX be approved for "improving luminal diameter for the treatment of de novo or restenotic symptomatic lesions in vascular disease of the above-the-knee femoropopliteal arteries," with reference vessel diameters from 4 mm to 9 mm and total lesion lengths measuring up to 140 mm/limb and 280 mm/patient. The same stent has been approved for use in femoropopliteal arteries in Europe since 2009, according to Cook.

If approved, it will be the first drug-eluting stent approved in the United States for treating femoropopliteal arteries.

The pivotal study, a randomized, controlled open-label trial in the United States, Japan, and Germany, enrolled almost 500 patients (mean age 68 years) with up to two stenotic or occluded atherosclerotic lesions of above-the knee femoropopliteal arteries (up to one in each limb), measuring a maximum of 14 cm or less in length, and randomized then to treatment with the Zilver PTX stent (240 patients) or percutaneous transluminal angioplasty (238). Patients whose angioplasty results were suboptimal (120) were randomized a second time to treatment with the Zilver bare metal stent (56 patients) or the Zilver PTX stent (64). Patients were treated with clopidogrel, which was started either before or during the procedure (patients in Japan received ticlopidine), and for 60 days after the procedure, with aspirin indefinitely.

At 12 months, the patency rate was 83% among those treated with the Zilver PTX stent, compared with 33% of those who had angioplasty. Among those who had been randomized a second time, the patency rate at 12 months was 90% among those who had the Zilver PTX stent, compared with 73% of those who received the Zilver BMS.

The primary safety end point was "event-free survival" at 12 months defined as "freedom" from death, target lesion revascularization, worsening symptoms, or ischemia of the target limb requiring surgery of the target vessel – which was 84% among those treated with angioplasty, compared with 90% of those treated with the Zilver PTX stent.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts before the meeting.

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel on Oct. 13 voted 11-0 that the benefits of a drug-eluting stent outweighed its risks as a treatment for patients with symptomatic atherosclerotic stenosis of the femoropopliteal arteries.

The FDA’s Circulatory System Devices Panel also unanimously voted that the available data provided "reasonable assurance" that the Zilver PTX drug-eluting stent (DES) was safe and effective for the proposed indication. The panel did not specifically vote on whether to recommend approval.

The Zilver PTX stent is a self-expanding, nitinol stent coated with paclitaxel, which is the active ingredient in the chemotherapy treatment Taxol and in the FDA-approved Taxus coronary stent. Its delivery system is the same as the one used with the Zilver vascular stent, a bare-metal stent (BMS) that is FDA approved for use in iliac arteries.

The Zilver PTX stent’s manufacturer, Cook Medical Inc., has proposed that the Zilver PTX be approved for "improving luminal diameter for the treatment of de novo or restenotic symptomatic lesions in vascular disease of the above-the-knee femoropopliteal arteries," with reference vessel diameters from 4 mm to 9 mm and total lesion lengths measuring up to 140 mm/limb and 280 mm/patient. The same stent has been approved for use in femoropopliteal arteries in Europe since 2009, according to Cook.

If approved, it will be the first drug-eluting stent approved in the United States for treating femoropopliteal arteries.

The pivotal study, a randomized, controlled open-label trial in the United States, Japan, and Germany, enrolled almost 500 patients (mean age 68 years) with up to two stenotic or occluded atherosclerotic lesions of above-the knee femoropopliteal arteries (up to one in each limb), measuring a maximum of 14 cm or less in length, and randomized then to treatment with the Zilver PTX stent (240 patients) or percutaneous transluminal angioplasty (238). Patients whose angioplasty results were suboptimal (120) were randomized a second time to treatment with the Zilver bare metal stent (56 patients) or the Zilver PTX stent (64). Patients were treated with clopidogrel, which was started either before or during the procedure (patients in Japan received ticlopidine), and for 60 days after the procedure, with aspirin indefinitely.

At 12 months, the patency rate was 83% among those treated with the Zilver PTX stent, compared with 33% of those who had angioplasty. Among those who had been randomized a second time, the patency rate at 12 months was 90% among those who had the Zilver PTX stent, compared with 73% of those who received the Zilver BMS.

The primary safety end point was "event-free survival" at 12 months defined as "freedom" from death, target lesion revascularization, worsening symptoms, or ischemia of the target limb requiring surgery of the target vessel – which was 84% among those treated with angioplasty, compared with 90% of those treated with the Zilver PTX stent.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts before the meeting.

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel on Oct. 13 voted 11-0 that the benefits of a drug-eluting stent outweighed its risks as a treatment for patients with symptomatic atherosclerotic stenosis of the femoropopliteal arteries.

The FDA’s Circulatory System Devices Panel also unanimously voted that the available data provided "reasonable assurance" that the Zilver PTX drug-eluting stent (DES) was safe and effective for the proposed indication. The panel did not specifically vote on whether to recommend approval.

The Zilver PTX stent is a self-expanding, nitinol stent coated with paclitaxel, which is the active ingredient in the chemotherapy treatment Taxol and in the FDA-approved Taxus coronary stent. Its delivery system is the same as the one used with the Zilver vascular stent, a bare-metal stent (BMS) that is FDA approved for use in iliac arteries.

The Zilver PTX stent’s manufacturer, Cook Medical Inc., has proposed that the Zilver PTX be approved for "improving luminal diameter for the treatment of de novo or restenotic symptomatic lesions in vascular disease of the above-the-knee femoropopliteal arteries," with reference vessel diameters from 4 mm to 9 mm and total lesion lengths measuring up to 140 mm/limb and 280 mm/patient. The same stent has been approved for use in femoropopliteal arteries in Europe since 2009, according to Cook.

If approved, it will be the first drug-eluting stent approved in the United States for treating femoropopliteal arteries.

The pivotal study, a randomized, controlled open-label trial in the United States, Japan, and Germany, enrolled almost 500 patients (mean age 68 years) with up to two stenotic or occluded atherosclerotic lesions of above-the knee femoropopliteal arteries (up to one in each limb), measuring a maximum of 14 cm or less in length, and randomized then to treatment with the Zilver PTX stent (240 patients) or percutaneous transluminal angioplasty (238). Patients whose angioplasty results were suboptimal (120) were randomized a second time to treatment with the Zilver bare metal stent (56 patients) or the Zilver PTX stent (64). Patients were treated with clopidogrel, which was started either before or during the procedure (patients in Japan received ticlopidine), and for 60 days after the procedure, with aspirin indefinitely.

At 12 months, the patency rate was 83% among those treated with the Zilver PTX stent, compared with 33% of those who had angioplasty. Among those who had been randomized a second time, the patency rate at 12 months was 90% among those who had the Zilver PTX stent, compared with 73% of those who received the Zilver BMS.

The primary safety end point was "event-free survival" at 12 months defined as "freedom" from death, target lesion revascularization, worsening symptoms, or ischemia of the target limb requiring surgery of the target vessel – which was 84% among those treated with angioplasty, compared with 90% of those treated with the Zilver PTX stent.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts before the meeting.

The Food and Drug Administration has approved Restylane for lip augmentation, the manufacturer announced Oct. 11.

The hyaluronic acid dermal filler was first approved in 2005 for mid to deep dermal implantation for the correction of moderate to severe facial wrinkles and folds, and has been used off-label for lip augmentation. Restylane (Medicis Aesthetics) is a hyaluronic acid gel generated by Streptococcus bacteria, chemically crosslinked with 1,4 butanediol diglycidyl ether.

At a meeting in April, an FDA advisory panel voted 6-0 with 1 abstention that the benefits of using the filler as a submucosal injection for lip augmentation outweighed its risks, and that the filler was safe and effective for the expanded indication.

At that meeting, the panel reviewed the results of a study of 135 patients who received lip augmentation with Restylane (with a mean filler volume of 2.9 cc per patient, with a range of 0.6-5.6 cc per patient) and 45 patients with no treatment. At 8 weeks, 92% of patients who received Restylane were considered responders; almost all patients (99%) experienced adverse events, which included expected treatment-emergent adverse events such as bruising, redness, swelling, pain, tenderness, itching, and skin exfoliation. Of those who were treated, 40% experienced adverse outcomes that they felt affected their daily activity or were disabling, and 15% experienced adverse events (typically swelling and tenderness) that lasted more than 15 days.

Among the concerns expressed by the panel was the lack of men and people with dark skin in the study.

The Food and Drug Administration has approved Restylane for lip augmentation, the manufacturer announced Oct. 11.

The hyaluronic acid dermal filler was first approved in 2005 for mid to deep dermal implantation for the correction of moderate to severe facial wrinkles and folds, and has been used off-label for lip augmentation. Restylane (Medicis Aesthetics) is a hyaluronic acid gel generated by Streptococcus bacteria, chemically crosslinked with 1,4 butanediol diglycidyl ether.

At a meeting in April, an FDA advisory panel voted 6-0 with 1 abstention that the benefits of using the filler as a submucosal injection for lip augmentation outweighed its risks, and that the filler was safe and effective for the expanded indication.

At that meeting, the panel reviewed the results of a study of 135 patients who received lip augmentation with Restylane (with a mean filler volume of 2.9 cc per patient, with a range of 0.6-5.6 cc per patient) and 45 patients with no treatment. At 8 weeks, 92% of patients who received Restylane were considered responders; almost all patients (99%) experienced adverse events, which included expected treatment-emergent adverse events such as bruising, redness, swelling, pain, tenderness, itching, and skin exfoliation. Of those who were treated, 40% experienced adverse outcomes that they felt affected their daily activity or were disabling, and 15% experienced adverse events (typically swelling and tenderness) that lasted more than 15 days.

Among the concerns expressed by the panel was the lack of men and people with dark skin in the study.

The Food and Drug Administration has approved Restylane for lip augmentation, the manufacturer announced Oct. 11.

The hyaluronic acid dermal filler was first approved in 2005 for mid to deep dermal implantation for the correction of moderate to severe facial wrinkles and folds, and has been used off-label for lip augmentation. Restylane (Medicis Aesthetics) is a hyaluronic acid gel generated by Streptococcus bacteria, chemically crosslinked with 1,4 butanediol diglycidyl ether.

At a meeting in April, an FDA advisory panel voted 6-0 with 1 abstention that the benefits of using the filler as a submucosal injection for lip augmentation outweighed its risks, and that the filler was safe and effective for the expanded indication.

At that meeting, the panel reviewed the results of a study of 135 patients who received lip augmentation with Restylane (with a mean filler volume of 2.9 cc per patient, with a range of 0.6-5.6 cc per patient) and 45 patients with no treatment. At 8 weeks, 92% of patients who received Restylane were considered responders; almost all patients (99%) experienced adverse events, which included expected treatment-emergent adverse events such as bruising, redness, swelling, pain, tenderness, itching, and skin exfoliation. Of those who were treated, 40% experienced adverse outcomes that they felt affected their daily activity or were disabling, and 15% experienced adverse events (typically swelling and tenderness) that lasted more than 15 days.

Among the concerns expressed by the panel was the lack of men and people with dark skin in the study.

An inhalation spray containing ipratropium bromide and albuterol sulfate had been approved for patients with chronic obstructive pulmonary disease, according to a statement issued Oct. 7 by the Food and Drug Administration.

The product, marketed as Combivent Respimat inhalation spray, does not contain chlorofluorocarbons (CFCs) and "is a suitable alternative for patients who are currently using Combivent (ipratropium bromide and albuterol sulfate) inhalation aerosol," according to the statement, issued by the Division of Drug Information (DDI) in the FDA’s Center for Drugs, Evaluation and Research (CDER). Combivent inhalation aerosol, which contains CFCs, will not be available after Dec. 31, 2013. Like other inhalers that contain CFCs that deplete the ozone layer, the inhaler is being phased out because of the Montreal Protocol on Substances that Deplete the Ozone Layer, which makes it illegal to sell or make substances that decrease the ozone layer.

Ipratropium is an anticholinergic bronchodilator, and albuterol is a selective beta 2 adrenergic bronchodilator. Combivent inhalers are indicated for people with COPD, on a regular bronchodilator, who continue to have evidence of bronchospasm and who require a second bronchodilator.

An inhalation spray containing ipratropium bromide and albuterol sulfate had been approved for patients with chronic obstructive pulmonary disease, according to a statement issued Oct. 7 by the Food and Drug Administration.

The product, marketed as Combivent Respimat inhalation spray, does not contain chlorofluorocarbons (CFCs) and "is a suitable alternative for patients who are currently using Combivent (ipratropium bromide and albuterol sulfate) inhalation aerosol," according to the statement, issued by the Division of Drug Information (DDI) in the FDA’s Center for Drugs, Evaluation and Research (CDER). Combivent inhalation aerosol, which contains CFCs, will not be available after Dec. 31, 2013. Like other inhalers that contain CFCs that deplete the ozone layer, the inhaler is being phased out because of the Montreal Protocol on Substances that Deplete the Ozone Layer, which makes it illegal to sell or make substances that decrease the ozone layer.

Ipratropium is an anticholinergic bronchodilator, and albuterol is a selective beta 2 adrenergic bronchodilator. Combivent inhalers are indicated for people with COPD, on a regular bronchodilator, who continue to have evidence of bronchospasm and who require a second bronchodilator.

An inhalation spray containing ipratropium bromide and albuterol sulfate had been approved for patients with chronic obstructive pulmonary disease, according to a statement issued Oct. 7 by the Food and Drug Administration.

The product, marketed as Combivent Respimat inhalation spray, does not contain chlorofluorocarbons (CFCs) and "is a suitable alternative for patients who are currently using Combivent (ipratropium bromide and albuterol sulfate) inhalation aerosol," according to the statement, issued by the Division of Drug Information (DDI) in the FDA’s Center for Drugs, Evaluation and Research (CDER). Combivent inhalation aerosol, which contains CFCs, will not be available after Dec. 31, 2013. Like other inhalers that contain CFCs that deplete the ozone layer, the inhaler is being phased out because of the Montreal Protocol on Substances that Deplete the Ozone Layer, which makes it illegal to sell or make substances that decrease the ozone layer.

Ipratropium is an anticholinergic bronchodilator, and albuterol is a selective beta 2 adrenergic bronchodilator. Combivent inhalers are indicated for people with COPD, on a regular bronchodilator, who continue to have evidence of bronchospasm and who require a second bronchodilator.

The erectile dysfunction drug tadalafil has been approved for treatment of the signs and symptoms of benign prostatic hyperplasia, the Food and Drug Administration announced on Oct. 6.

Tadalafil, the phosphodiesterase-5 (PDE5) inhibitor marketed as Cialis by Eli Lilly, was also approved for treating BPH and erectile dysfunction (ED), when they occur simultaneously, according to the FDA statement. The agency first approved tadalafil for treating erectile dysfunction in 2003.

Men with BPH have an enlarged prostate, which can cause symptoms ranging from difficulty urinating and a weak urine stream to a sudden urge to urinate and more frequent urination.

In two studies of men with BPH, those treated with 5 mg/day of tadalafil experienced statistically significant improvements in symptoms, as indicated by reductions in the total International Prostate Symptom Score (IPSS), when compared with the score in men who received a placebo.

Similarly, in a placebo-controlled study of men with both ED and BPH, those treated with 5 mg/day of tadalafil had improvements in symptoms of both conditions, with the ED improvement measured by the erectile function domain score of the International Index of Erectile Function.

The FDA noted that tadalafil is contraindicated in patients taking nitrates, such as nitroglycerin, because it has been shown to potentiate the hypotensive effects of nitrates. In addition, combining tadalafil with alpha-blockers for treating BPH "is not recommended because the combination has not been adequately studied for the treatment of BPH, and there is a risk of lowering blood pressure," the statement said.

Tadalafil is the first PDE5 inhibitor to be approved for BPH. The eight drugs previously approved for treating BPH symptoms are the 5-alpha reductase inhibitors finasteride (Proscar) and dutasteride (Avodart); alpha-blockers terazosin (Hytrin), doxazosin (Cardura), tamsulosin (Flomax), alfuzosin (Uroxatral), and silodosin (Rapaflo); and the combination of dutasteride plus tamsulosin (Jalyn).

The erectile dysfunction drug tadalafil has been approved for treatment of the signs and symptoms of benign prostatic hyperplasia, the Food and Drug Administration announced on Oct. 6.

Tadalafil, the phosphodiesterase-5 (PDE5) inhibitor marketed as Cialis by Eli Lilly, was also approved for treating BPH and erectile dysfunction (ED), when they occur simultaneously, according to the FDA statement. The agency first approved tadalafil for treating erectile dysfunction in 2003.

Men with BPH have an enlarged prostate, which can cause symptoms ranging from difficulty urinating and a weak urine stream to a sudden urge to urinate and more frequent urination.

In two studies of men with BPH, those treated with 5 mg/day of tadalafil experienced statistically significant improvements in symptoms, as indicated by reductions in the total International Prostate Symptom Score (IPSS), when compared with the score in men who received a placebo.

Similarly, in a placebo-controlled study of men with both ED and BPH, those treated with 5 mg/day of tadalafil had improvements in symptoms of both conditions, with the ED improvement measured by the erectile function domain score of the International Index of Erectile Function.

The FDA noted that tadalafil is contraindicated in patients taking nitrates, such as nitroglycerin, because it has been shown to potentiate the hypotensive effects of nitrates. In addition, combining tadalafil with alpha-blockers for treating BPH "is not recommended because the combination has not been adequately studied for the treatment of BPH, and there is a risk of lowering blood pressure," the statement said.

Tadalafil is the first PDE5 inhibitor to be approved for BPH. The eight drugs previously approved for treating BPH symptoms are the 5-alpha reductase inhibitors finasteride (Proscar) and dutasteride (Avodart); alpha-blockers terazosin (Hytrin), doxazosin (Cardura), tamsulosin (Flomax), alfuzosin (Uroxatral), and silodosin (Rapaflo); and the combination of dutasteride plus tamsulosin (Jalyn).

The erectile dysfunction drug tadalafil has been approved for treatment of the signs and symptoms of benign prostatic hyperplasia, the Food and Drug Administration announced on Oct. 6.

Tadalafil, the phosphodiesterase-5 (PDE5) inhibitor marketed as Cialis by Eli Lilly, was also approved for treating BPH and erectile dysfunction (ED), when they occur simultaneously, according to the FDA statement. The agency first approved tadalafil for treating erectile dysfunction in 2003.

Men with BPH have an enlarged prostate, which can cause symptoms ranging from difficulty urinating and a weak urine stream to a sudden urge to urinate and more frequent urination.

In two studies of men with BPH, those treated with 5 mg/day of tadalafil experienced statistically significant improvements in symptoms, as indicated by reductions in the total International Prostate Symptom Score (IPSS), when compared with the score in men who received a placebo.

Similarly, in a placebo-controlled study of men with both ED and BPH, those treated with 5 mg/day of tadalafil had improvements in symptoms of both conditions, with the ED improvement measured by the erectile function domain score of the International Index of Erectile Function.

The FDA noted that tadalafil is contraindicated in patients taking nitrates, such as nitroglycerin, because it has been shown to potentiate the hypotensive effects of nitrates. In addition, combining tadalafil with alpha-blockers for treating BPH "is not recommended because the combination has not been adequately studied for the treatment of BPH, and there is a risk of lowering blood pressure," the statement said.

Tadalafil is the first PDE5 inhibitor to be approved for BPH. The eight drugs previously approved for treating BPH symptoms are the 5-alpha reductase inhibitors finasteride (Proscar) and dutasteride (Avodart); alpha-blockers terazosin (Hytrin), doxazosin (Cardura), tamsulosin (Flomax), alfuzosin (Uroxatral), and silodosin (Rapaflo); and the combination of dutasteride plus tamsulosin (Jalyn).

A warning about the risk of ovarian failure in premenopausal women has been added to the label for bevacizumab, along with new postmarketing data identifying osteonecrosis of the jaw as an "adverse reaction," the Food and Drug Administration announced on Oct. 4.

Information about the increased risk of venous thromboembolic events (VTEs) and bleeding associated with bevacizumab in patients receiving anticoagulation therapy after a first VTE event has also been added in the section on Clinical Trial Experience, the FDA said.

Bevacizumab – marketed as Avastin by Genentech, a member of the Roche group – is a vascular endothelial growth factor inhibitor approved for the treatment of several different cancers, as a single agent or in combination with other treatments. It was first approved in 2004; a controversial FDA move to withdraw an indication in metastatic breast cancer is pending.

The potential for ovarian failure associated with bevacizumab treatment in premenopausal women is new information. It has been added to the warnings and precautions section of the label and in a new "Females of Reproductive Potential" subsection.

The information includes the results of a study of that found new cases of ovarian failure in 34% of women with stage II and III colorectal cancer treated with bevacizumab plus mFOLFOX (5-fluorouracil, leucovorin, oxaliplatin) chemotherapy, compared with 2% of women on chemotherapy alone – a 14-fold increase in relative risk. After treatment was stopped, recovery of ovarian function was documented in 22% of the women with ovarian failure.

This section now states that the long-term effects of exposure to bevacizumab on fertility are unknown and that women of reproductive potential should be informed about the risk of ovarian failure before starting treatment.

The postmarketing experience section of the label now includes a statement about postmarketing reports of osteonecrosis of the jaw (ONJ) in patients treated with bevacizumab who have not been treated with bisphosphonates (ONJ has been reported in patients on bisphosphonates).

The statement says that the pathogenesis of ONJ is not clear and that "it is possible that the antiangiogenic properties of bevacizumab may result in bone tissue avascularization leading to ischemic changes in the microvasculature of the jaw, resulting in osteonecrosis."

The new information on VTEs summarizes the results of a randomized, prospective four-arm study of 1,401 patients with mCRC that evaluated the VTE incidence. Among those in the bevacizumab-containing arms, the incidence of a first VTE was 13.5%, compared with 9.6% among the patients in the chemotherapy-only arms.

The overall incidence of subsequent VTEs was also higher with bevacizumab in a subgroup analysis of patients that received anticoagulants after an initial VTE event: The subsequent VTE rate was 31.5% among those in the bevacizumab-containing arms, compared with 25.6% among those in the chemotherapy-only arms.

Among patients treated with anticoagulants, the overall incidence of bleeding was also higher in the bevacizumab-containing arms, compared with the chemotherapy-only arms: 27.4% vs. 20.9%, respectively.

The label already included a boxed warning about the increased risk of gastrointestinal perforations, surgery and wound healing complications, and hemorrhage associated with bevacizumab, an angiogenesis inhibitor designed to interfere with the growth of new blood vessels feeding tumors.

Serious adverse events associated with bevacizumab should be reported to the FDA’s MedWatch program at 800-332-1088.

A warning about the risk of ovarian failure in premenopausal women has been added to the label for bevacizumab, along with new postmarketing data identifying osteonecrosis of the jaw as an "adverse reaction," the Food and Drug Administration announced on Oct. 4.

Information about the increased risk of venous thromboembolic events (VTEs) and bleeding associated with bevacizumab in patients receiving anticoagulation therapy after a first VTE event has also been added in the section on Clinical Trial Experience, the FDA said.

Bevacizumab – marketed as Avastin by Genentech, a member of the Roche group – is a vascular endothelial growth factor inhibitor approved for the treatment of several different cancers, as a single agent or in combination with other treatments. It was first approved in 2004; a controversial FDA move to withdraw an indication in metastatic breast cancer is pending.

The potential for ovarian failure associated with bevacizumab treatment in premenopausal women is new information. It has been added to the warnings and precautions section of the label and in a new "Females of Reproductive Potential" subsection.

The information includes the results of a study of that found new cases of ovarian failure in 34% of women with stage II and III colorectal cancer treated with bevacizumab plus mFOLFOX (5-fluorouracil, leucovorin, oxaliplatin) chemotherapy, compared with 2% of women on chemotherapy alone – a 14-fold increase in relative risk. After treatment was stopped, recovery of ovarian function was documented in 22% of the women with ovarian failure.

This section now states that the long-term effects of exposure to bevacizumab on fertility are unknown and that women of reproductive potential should be informed about the risk of ovarian failure before starting treatment.

The postmarketing experience section of the label now includes a statement about postmarketing reports of osteonecrosis of the jaw (ONJ) in patients treated with bevacizumab who have not been treated with bisphosphonates (ONJ has been reported in patients on bisphosphonates).

The statement says that the pathogenesis of ONJ is not clear and that "it is possible that the antiangiogenic properties of bevacizumab may result in bone tissue avascularization leading to ischemic changes in the microvasculature of the jaw, resulting in osteonecrosis."

The new information on VTEs summarizes the results of a randomized, prospective four-arm study of 1,401 patients with mCRC that evaluated the VTE incidence. Among those in the bevacizumab-containing arms, the incidence of a first VTE was 13.5%, compared with 9.6% among the patients in the chemotherapy-only arms.

The overall incidence of subsequent VTEs was also higher with bevacizumab in a subgroup analysis of patients that received anticoagulants after an initial VTE event: The subsequent VTE rate was 31.5% among those in the bevacizumab-containing arms, compared with 25.6% among those in the chemotherapy-only arms.

Among patients treated with anticoagulants, the overall incidence of bleeding was also higher in the bevacizumab-containing arms, compared with the chemotherapy-only arms: 27.4% vs. 20.9%, respectively.

The label already included a boxed warning about the increased risk of gastrointestinal perforations, surgery and wound healing complications, and hemorrhage associated with bevacizumab, an angiogenesis inhibitor designed to interfere with the growth of new blood vessels feeding tumors.

Serious adverse events associated with bevacizumab should be reported to the FDA’s MedWatch program at 800-332-1088.

A warning about the risk of ovarian failure in premenopausal women has been added to the label for bevacizumab, along with new postmarketing data identifying osteonecrosis of the jaw as an "adverse reaction," the Food and Drug Administration announced on Oct. 4.

Information about the increased risk of venous thromboembolic events (VTEs) and bleeding associated with bevacizumab in patients receiving anticoagulation therapy after a first VTE event has also been added in the section on Clinical Trial Experience, the FDA said.

Bevacizumab – marketed as Avastin by Genentech, a member of the Roche group – is a vascular endothelial growth factor inhibitor approved for the treatment of several different cancers, as a single agent or in combination with other treatments. It was first approved in 2004; a controversial FDA move to withdraw an indication in metastatic breast cancer is pending.

The potential for ovarian failure associated with bevacizumab treatment in premenopausal women is new information. It has been added to the warnings and precautions section of the label and in a new "Females of Reproductive Potential" subsection.

The information includes the results of a study of that found new cases of ovarian failure in 34% of women with stage II and III colorectal cancer treated with bevacizumab plus mFOLFOX (5-fluorouracil, leucovorin, oxaliplatin) chemotherapy, compared with 2% of women on chemotherapy alone – a 14-fold increase in relative risk. After treatment was stopped, recovery of ovarian function was documented in 22% of the women with ovarian failure.

This section now states that the long-term effects of exposure to bevacizumab on fertility are unknown and that women of reproductive potential should be informed about the risk of ovarian failure before starting treatment.

The postmarketing experience section of the label now includes a statement about postmarketing reports of osteonecrosis of the jaw (ONJ) in patients treated with bevacizumab who have not been treated with bisphosphonates (ONJ has been reported in patients on bisphosphonates).

The statement says that the pathogenesis of ONJ is not clear and that "it is possible that the antiangiogenic properties of bevacizumab may result in bone tissue avascularization leading to ischemic changes in the microvasculature of the jaw, resulting in osteonecrosis."

The new information on VTEs summarizes the results of a randomized, prospective four-arm study of 1,401 patients with mCRC that evaluated the VTE incidence. Among those in the bevacizumab-containing arms, the incidence of a first VTE was 13.5%, compared with 9.6% among the patients in the chemotherapy-only arms.

The overall incidence of subsequent VTEs was also higher with bevacizumab in a subgroup analysis of patients that received anticoagulants after an initial VTE event: The subsequent VTE rate was 31.5% among those in the bevacizumab-containing arms, compared with 25.6% among those in the chemotherapy-only arms.

Among patients treated with anticoagulants, the overall incidence of bleeding was also higher in the bevacizumab-containing arms, compared with the chemotherapy-only arms: 27.4% vs. 20.9%, respectively.

The label already included a boxed warning about the increased risk of gastrointestinal perforations, surgery and wound healing complications, and hemorrhage associated with bevacizumab, an angiogenesis inhibitor designed to interfere with the growth of new blood vessels feeding tumors.

Serious adverse events associated with bevacizumab should be reported to the FDA’s MedWatch program at 800-332-1088.