Evelyn Pringle April 26, 2006
On April 27, 2006, Dow Jones reported that Bristol-Myers Squibb had decided to stop selling Tequin, an antibiotic found to increase the risk of blood-sugar problems.
BMS made a "recent decision to stop all our commercialization efforts" for Tequin and to return the rights to Kyorin, Dow quoted Chief Financial Officer, Andrew Bonfield, as saying.
BMS licensed the drug from Kyorin Pharmaceutical of Japan in 1996 and obtained FDA approval sell the drug in the US in December 1999.
A much more believable explanation for pulling Tequin off the market is that BMS is anticipating the filing of an infinite number of lawsuits against the company in the near future so it figured it was a good idea to get out of Dodge.
Tequin, (Gatifloxacin) belongs to the class of antibiotics known as fluoroquinolones, typically used to treat lung, sinus and urinary tract infections and certain sexually transmitted diseases.
This class of drugs has a long history of serious side effects. In fact, the following fluoroquinolones are either under use restriction, or have been removed from the market: (1) temafloxacin due to red blood cell damage, kidney failure and hypoglycemia; (2) grepafloxacin because of heart problems; and (3) trovafloxacin due to liver damage.
If BMS is to be believed, it was not aware of any serious side effects associated with Tequin when it was approved for use in the US. In a September 20, 2000 press release, the company announced that in the first 6 months, Tequin had been prescribed for more than 500,000 patients in the US within 6 months after it was approved by the FDA on December 17, 1999.
It bragged that Tequin was the first quinolone antibiotic to achieve this milestone during the first 6 months on the market, citing audited data reported in June, 2000, by IMS Health, a supplier of market research to the pharmaceutical industry
By September 2000, the press release said, Tequin had been prescribed to more than 800,000 patients in the US and more than 1 million patients worldwide.
And as a result, company profits skyrocketed. According to Bristol's 2004 Annual Report, in 2003, sales of Tequin increased by 13% to $208 million, up from $184 million in 2002.
In September 20, press release, BMS said the most common side effects associated with Tequin in clinical trials were gastrointestinal and adverse reactions "considered to be drug related and occurring in greater than or equal to three percent were: nausea (8%), vaginitis (6%), diarrhea (4%), headache (3%) and dizziness (3%)."
In a January 28, 2000, press release, the company said Tequin "has been shown in clinical trials to provide excellent efficacy and tolerability."
Not a peep was heard about the serious adverse reactions that have since been revealed.
However, BMS has been aware of most of Tequin's side effects for years. For instance, an article about the glucose disorders associated with the drug was published by Health Canada in the Canadian Adverse Reaction Newsletter in July 2003.
The article discussed a postmarketing study on the use of Gatifloxacin with more than 15,000 patients and reported the incidence of hypoglycemic events as 0.3 per 1000 among nondiabetic patients and 6.4 per 1000 in patients who were diabetic.
The rate of hyperglycemia found in the study was 0.07 per 1000 in nondiabetics, and 13 per 1000 in diabetic patients.
By 2002, Health Canada's database of spontaneous reports of adverse reactions indicated that hypoglycemia and hyperglycemia had been reported more frequently with gatifloxacin than with any other quinolone antibiotics, according to Parilo MA. Gatifloxacin-associated hypoglycemia, J Pharm Technol 2002;18:319-20.
Health Canada received 28 reports of abnormal glucose metabolism associated with Gatifloxacin (44% of total reports received for the drug) from February 21, 2001 (date marketed in Canada), to February 28, 2003: 19 were for hypoglycemia, 7 were reported hyperglycemia, and 2 involved both hypoglycemia and hyperglycemia.
Twenty-five of the cases involved patients with type 2 diabetes, 2 involved nondiabetic patients, and in 1 case the patient's diabetic status was unknown.
Of the 28 cases, 19 of the patients were admitted to hospital or had a prolonged hospital stay because of the reaction. The 2 patients who died had hyperglycemia, and had no prior history of diabetes or decreased renal function at the time of the reaction.
The Canadian product monograph for Tequin was updated in December 2002, in response to the reported cases of serious, life-threatening disturbances of glucose homeostasis.
In December 2005, Health Canada, citing evidence indicating of glucose disorders, asked BMS to submit revised product information for Tequin. BMS submitted information for review, but Health Canada noted that given the availability of other antibiotics, patients with diabetes should be prescribed alternative antibiotics while the agency was reviewing the data.
Also in December 2005, according to Health Canada, BMS issued a letter to Canadian health care providers and a public health advisory about a possible link between the antibiotic and blood glucose disorders, after serious cases of both low blood sugar and high blood sugar were reported in patients worldwide.
In February 2006, the FDA finally entered the fray and joined Health Canada in announcing that BMS had informed doctors that Tequin should not be used with diabetics, and that elderly patients, as well as those with kidney problems, were more likely to experience serious side effects.
Also in February, BMS revised Tequin's label in the US to warn of the potential fatal risks of high and low blood-sugar levels and recommended against the use of the drug by diabetics.
The changes were said to be made in response to the results of 2 studies conducted by a team of Canadian scientists from the Institute of Clinical Evaluative Sciences, published in the New England Journal of Medicine.
The first study involved 788 patients over the age of 66, who received treatments for hypoglycemia within 30 days after antibiotic therapy, and the second involved 470 patients in the same age group who were treated for hyperglycemia within 30 days after antibiotic therapy.
When compared to other antibiotics, the use of Tequin was found to be linked to a 4.3 times greater risk of hypoglycemia, and a 16.7 times higher risk of hyperglycemia. The increased risks were present in both diabetic and non-diabetic patients.
BMS and the FDA feigned shock over these findings but in reality, the numbers were not that much higher than those reported above by Health Canada in 2002.
Experts say Tequin patients should be alerted to the signs of blood sugar problems which can include:
Confusion
Visual disturbances
Heart palpitations
Tremors
Frequent urination
Increased thirst
Dry mouth
Back in December 2001, other serious long-term side effects associated with fluoroquinolones were reported by, Dr Jay Cohen, MD, President and Executive Director of the Center for the Prevention of Medication Side Effects, in a study published in the Annals of Pharmachotherapy.
In his study, Dr Cohen found that severe reactions were occurring in young, healthy, and active patients, who often were receiving antibiotic therapy for mild infections such as sinusitis, urinary tract or prostate infections.
In most cases, Dr Cohen noted, side effects were multiple, involving many systems of the body including reports that nervous system symptoms occurred in 91% of the patients, musculoskeletal in 73%, sensory system in 42% of the subjects, cardiovascular symptoms in 36%, skin reactions in 29%, and gastrointestinal symptoms in 18% of the patients.
The fluoroquinolone class of antibiotics includes: ciprofloxacin (Arflox, C-Flox, Ciloxan, Ciloquin, Ciproxin, Ciprol, Profloxin, Proquin, Procip, Ciprobay, Ciaxone); norfloxacin (Insensye, Norflohexal, Noroxin, Nufloxib, Roxin); gatifloxacin (Tequin); moxifloxacin (Avelox); as well as several other generic versions of ciprofloxacin and norfloxacin.
Another serious side effect experienced by patients using Tequin involves tendon disorders. A February 2006, Australian Adverse Drug Reaction Bulletin, reported an increased risk of tendinitis and even tendon rupture with all fluoroquinolones.
Of the 213 reported cases of tendinitis or tendon rupture, more than 80% involved fluroquinolones, the Bulletin said.
"Patients should be advised to be alert for pain or discomfort in the Achilles tendon or calf," the Bulletin warned, "and to inform their doctors and cease taking the medicine if this occurs."
In September 2004, the FDA announced label changes for Tequin to include warnings of (1) QTc Interval Prolongation; (2) Tendon Effects; and (3) Peripheral Neuropathy and added descriptions of these 3 adverse reaction to the patient package inserts.
For QTc interval prolongation, the insert states: "Gatifloxacin has the potential to prolong the QTc interval of the electrocardiogram in some patients. QTc prolongation may lead to an increased risk for ventricular arrhythmias including torsades de pointes."
On peripheral neuropathy, the insert notes: "Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones."
And for tendon effects, the insert states: "Ruptures of the shoulder, hand, Achilles tendon, or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including levofloxacin."
In light of the serious injuries now linked to the drug, it might have been a wise decision on the part of BMS to get Tequin out of Dodge.
Showing posts with label Bristol-Myers. Show all posts
Showing posts with label Bristol-Myers. Show all posts
Wednesday, August 4, 2010
Tuesday, August 3, 2010
Tequin - Blood-Sugar Problems Ain't All
Evelyn Pringle March 17, 2006
The antibiotic, Tequin, manufactured by Bristol Myers Squibb, has been linked to both hypoglycemia and hyperglycemia by researchers who examined treatment outcomes associated with various antibiotics in approximately 1.4 million patients, 66 years of age and older, between April 2002 and March 2004.
A team of Canadian scientists from the Institute of Clinical Evaluative Sciences, recently reported the results of their study in the New England Journal of Medicine.
Worldwide, Tequin (gatifloxacin) is a commonly used drug. In 2004, over 30 companies were marketing the antibiotic under brand names like Gaticin, Gatilox, Gatiquin, Gatoxc and Microgat. The Canadian scientists reported that on an average, Tequin is prescribed about 500 times a day in Canada.
Tequin is a member of the class of antibiotics called fluoroquinolones. According to the Mayo Clinic web site, the drug is used to treat many different bacterial infections including pneumonia, bronchitis, sinus infections, respiratory tract infections, urinary tract infections and certain sexually transmitted diseases. Some of the other antibiotics in this class include Cipro (ciprofloxacin), Floxin (ofloxacin), and Levaquin (levofloxacin).
The Canadian findings were the result of two population-based, case-control studies. For each patient, the researchers identified up to 5 controls matched according to sex, age, the presence or absence of diabetes, and the timing of antibiotic treatment.
In the first study, 788 patients were identified who had been treated in the hospital for hypoglycemia (low blood sugar) within 30 days of receiving outpatient treatment with either a macrolide, a second-generation cephalosporin antibiotic, or a respiratory fluoroquinolone antibiotic (gatifloxacin, levofloxacin, moxifloxacin, or ciprofloxacin).
The use of Tequin was linked with a 4.3 times higher risk of hypoglycemia and a small increased risk of low blood sugar was also found with Levaquin. There was no increased risk shown with any of the other antibiotics examined.
In the second study, 470 patients were identified who received hospital care for hyperglycemia (high blood sugar) within 30 days after antibiotic therapy. When compared with macrolides, Tequin was associated with a 16.7 times higher risk of hyperglycemia, while no risk was noted with the other antibiotics.
Within the groups, there were 61 Tequin recipients with hypoglycemia and 86 with hyperglycemia. Overall, one of every 100 patients who took the drug was hospitalized.
The increased risks were similar in both groups of patients regardless of the previous presence or absence of diabetes.
"As compared with the use of other broad-spectrum oral antibiotics, including other fluoroquinolones," the study concluded, "the use of gatifloxacin among outpatients is associated with an increased risk of in-hospital treatment for both hypoglycemia and hyperglycemia."
The importance of these findings prompted the New England Journal of Medicine to make the study available online nearly a month in advance of its regular publication date of March 30, 2006. Changes in blood sugar levels can induce coma and other serious problems, including death.
The Mayo Clinic say patients taking Tequin need to be aware of the signs and symptoms of blood sugar fluctuations which include:
Confusion
Visual disturbances
Heart palpitations
Tremors
Frequent urination
Increased thirst
Dry mouth
In February 2006, Health Canada and the FDA issued advisory statements that said Bristol-Myers had told doctors that Tequin should not be used with diabetics, and that patients with kidney problems were more likely to experience serious side effects from the drug. The public health agencies also announced label changes for Tequin to include stronger warnings about the drug's link to blood-sugar related problems.
The editorial, "Serious Adverse Drug Effects - Seeing the Trees through the Forest," by Dr Jerry Gurwitz from the Meyers Primary Care Institute in Worcester, MA appears with the NEJM online study and says the FDA should consider mandating a "black-box" warning for Tequin's label or package insert.
"For every approved indication for [Tequin], there are safer, equally effective and less costly alternatives," Dr Gurwitz wrote in the editorial.
However, Dr David Juurlink, one of the Canadian researchers involved in the study, does not believe stronger warning labels are enough. He urges doctors not to prescribe Tequin at all.
"There are multiple alternatives," he says, "that are just as good and do not have this set of side effects that is unpredictable and potentially life threatening," according to the March 2, 2006 Wall Street Journal.
The actual number of blood-sugar risks are estimated to be much higher than listed in the study. Dr Juurlink was quoted by Reuters on March 1, 2006 as saying: "We can't identify everybody, only those who survived [a seizure from low blood sugar and made it] to the hospital or those sick enough to go to the hospital."
"If they died at home or in a pre-hospital setting, they would not have made it into the study," he said in the March 2, 2006 LA Times.
In the US, Tequin labeling has repeatedly changed over time based on other reports indicating that the antibiotic could dramatically alter blood sugar levels.
It came on the market in 1999, and by 2001, 3.3 million prescriptions per year were being written for the drug. Researchers began noticing problems that year, particularly alterations in glucose metabolism, according to the Times.
By 2003, 17 deaths had been linked to Tequin and prescriptions dropped to about 1.7 million per year.
One major contributor to that number, according to the Times, is the Department of Veterans Affairs, which added the drug to its formulary, designated an antibiotic of first choice, in part because Bristol-Myers offered the government a deal price of $1.35 per pill, verses the $8 to $10 per pill charged for Tequin and other fluoroquinolones at pharmacies, said Dr. Richard Frothingham of Duke University, according to the Times.
The government also chose Tequin because its risk of glucose abnormalities did not seem to be any higher than other antibiotics in the class, Dr Juurlink said. In light of the new findings, he told the Times, "the VA needs to very promptly revisit their policy."
Other adverse effects have also contributed to the withdrawal or restriction of several other drugs in this class of antibiotics including kidney failure and liver problems, according to the Mayo Clinic web site.
In addition, a wide range of neurological adverse effects linked to the fluoroquinolone antibiotics, reportedly found to occur in as many as 7% of patients, are described in a medical study conducted in 2001. These side effect symptoms include pins and needles, numbness, tingling, muscle and joint pain, palpitations, malaise, panic attacks, and anxiety, according to the study, "Peripheral Neuropathy Associated with Fluoroquinolones," by Jay S. Cohen, MD, in the December 2001, issue of The Annals of Pharmacotherapy, Volume 35.
Dr Cohen, President and Executive Director of the Center for the Prevention of Medication Side Effects, authored the study on long-term reactions to fluoroquinolones and the results were pre-released in October 2001, during the anthrax scare when Cipro was being widely prescribed without proper warnings to patients.
Within days of the publication, Dr Cohen says the CDC changed their guidelines and listed doxycycline and penicillin antibiotics as the preferred treatment for anthrax exposure before Cipro.
Doxycycline and penicillin were associated with much fewer serious side effects than fluoroquinolones, and were not linked to the disabling and long-term reactions identified in the study.
In most cases, he says side effects were multiple and involved many systems of the body.
The study found nervous system symptoms occurred in 91% of the patients, sensory system symptoms in 42%, musculoskeletal side effects in 73%, cardiovascular adverse effects in 36%, skin reactions in 29%, and gastrointestinal symptoms in 18% of the patients.
Dr Cohen found it especially alarming that severe reactions were occurring in patients who were young, healthy, and active, and most often were receiving antibiotic treatment for mild infections such as sinusitis, urinary or prostate infections. Most reactions occurred quickly, sometimes with just a few doses of the antibiotic.
For example, a male patient, age 36, previously in good health, ended up with chronic, debilitating multi-focal neuropathy, fibromyalgia, chronic fatigue, gastrointestinal problems, heart arrhythmia requiring pacemaker, carpal tunnel syndrome, chronic multiple joint pains, and chronic pain. Five years later at age 41, the patient was still disabled.
A previously healthy 32-year-old female patient was treated for a urinary infection and after 5 days, developed pain in wrists, neck, back, knees, hips, elbows, shoulders, and Achilles tendons.
A 34-year-old healthy male, was treated for a prostate infection and experienced side effects that included muscle spasms and twitching, numbness, impaired coordination, weakness, increased sensitivity to temperatures, fatigue, multiple joint, muscle pain, palpitations, and blurred vision for more than 1 year.
A 47-year-old female patient who was previously in good health, sought treatment for sinusitis and within 2 days of taking the antibiotic, developed severe joint pain in her hands, insomnia, severe agitation, weakness, dizziness, severe fatigue, mental infusion, abnormal dreams, and gastrointestinal symptoms, with many of the adverse effects listed as still severe after 7 months.
Another woman aged 49, with previous good health, received antibiotics for a pelvic infection that resulted in burning pain, memory loss, joint pains, palpitations, nerve pain, insomnia, abnormal sense of smell, tinnitis, and panic attacks for a duration of more than 3 years.
Another 35-year-old male, in good health, received treatment for a prostate infection and after one dose of medication he experienced ringing in the ears and peripheral nerve symptoms that lasted 2 weeks. He then developed tendonitis in his shoulders, elbows, wrists, hands, and Achilles tendons, with burning pain and tightness in his calves. This man was still unable to walk more than a short distance 2 months later.
"Prior to taking the medication I asked about side effects and was told there were none for adults except an upset stomach," this patient told Dr Cohen. "Afterwards I was told that what I was experiencing could not be related to the drug," he said.
Denying the link between the adverse events and the fluoroquinolones is apparently common. "In most cases," Dr Cohen says, "their doctors have dismissed their complaints or outright deny that the reactions could occur with fluoroquinolones."
"Yet extensive medical workups do not find any other cause," he reports.
"Worse, there are no known effective treatments," he says. "Thus, these people suffer pain and disability for weeks, months, years."
"Overall, my sense is that these reactions are not rare," Dr Cohen advises.
"Patients have a right of informed consent, and this includes warnings of potential serious, disabling reactions," he notes.
"Most of all," he warns, "we must educate doctors to avoid prescribing fluoroquinolones for minor infections, instead saving them for serious infections, just as we do with other groups of antibiotics with serious toxicities."
In the January 8, 2002 article titled, "Side Effects of Quinolone Antibiotics Like Tequin (Gatifloxacin) Can Be Serious," Mary Shomen gives a first-hand account of how varied and frightening some of the Tequin side effects can be.
Ms Shomen was prescribed Tequin for a sinus infection at an urgent care clinic and within one day experienced dizziness, tingling in her hands and knees, pain in her legs, and weakness in her arms and legs. A day later she says shortness of breath set in.
"I thought my symptoms might be related to my sinus infection," she wrote, "until I realized that they went away at night, and would start up again about an hour after taking my morning Tequin pill."
After four days Ms Shomen said, "I started having worsening shortening of breath, and difficulty swallowing, so I took two Beneadryl and called the doctor."
The call to the doctor resulted in a trip to the emergency room to see whether she was having a life-threatening allergic reaction to Tequin. At the hospital they discovered her airways were swollen so she was instructed to stay on Benadryl for 2 days.
"In the meantime," Ms Shomen recounts, "the tingling, numbness, difficulty swallowing and other neurological symptoms continued."
Four days later she says her memory was shot and she was still experiencing the tingling, numbness and dizziness. "After a night-time emergency call to my regular physician," she notes, "she suggested that I take some clonazepam (Klonopin), a mild tranquilizer, to see if that could calm down the overreactive nervous system."
The Klonopin calmed the symptoms and the doctor recommended that she remain on the drug until the side effects fully subsided.
"What I had was a dangerous - and even potentially life-threatening - drug reaction," Ms Shomen explains. "Who knows what might have happened had I not taken the Benadryl - an antihistimine - when the shortness of breath and airway constriction began?"
On March 1, 2006, Reuters reported that Bristol-Myers spokesman, Eric Miller said the company had decided to stop actively marketing Tequin, although his comments seemed to imply that the decision was based on economics rather than safety concerns.
Mr Miller noted that although Tequin was introduced onto the market in 1999, it only generated $150 million in sales for Bristol-Myers in 2005.
However, Bristol-Meyers choices related to the sale of Tequin may be limited. According to the editorial accompanying the study in the online NEJM. "It seems clear that the drug's place among broad-spectrum antibiotics available for outpatient use is tenuous at best."
The antibiotic, Tequin, manufactured by Bristol Myers Squibb, has been linked to both hypoglycemia and hyperglycemia by researchers who examined treatment outcomes associated with various antibiotics in approximately 1.4 million patients, 66 years of age and older, between April 2002 and March 2004.
A team of Canadian scientists from the Institute of Clinical Evaluative Sciences, recently reported the results of their study in the New England Journal of Medicine.
Worldwide, Tequin (gatifloxacin) is a commonly used drug. In 2004, over 30 companies were marketing the antibiotic under brand names like Gaticin, Gatilox, Gatiquin, Gatoxc and Microgat. The Canadian scientists reported that on an average, Tequin is prescribed about 500 times a day in Canada.
Tequin is a member of the class of antibiotics called fluoroquinolones. According to the Mayo Clinic web site, the drug is used to treat many different bacterial infections including pneumonia, bronchitis, sinus infections, respiratory tract infections, urinary tract infections and certain sexually transmitted diseases. Some of the other antibiotics in this class include Cipro (ciprofloxacin), Floxin (ofloxacin), and Levaquin (levofloxacin).
The Canadian findings were the result of two population-based, case-control studies. For each patient, the researchers identified up to 5 controls matched according to sex, age, the presence or absence of diabetes, and the timing of antibiotic treatment.
In the first study, 788 patients were identified who had been treated in the hospital for hypoglycemia (low blood sugar) within 30 days of receiving outpatient treatment with either a macrolide, a second-generation cephalosporin antibiotic, or a respiratory fluoroquinolone antibiotic (gatifloxacin, levofloxacin, moxifloxacin, or ciprofloxacin).
The use of Tequin was linked with a 4.3 times higher risk of hypoglycemia and a small increased risk of low blood sugar was also found with Levaquin. There was no increased risk shown with any of the other antibiotics examined.
In the second study, 470 patients were identified who received hospital care for hyperglycemia (high blood sugar) within 30 days after antibiotic therapy. When compared with macrolides, Tequin was associated with a 16.7 times higher risk of hyperglycemia, while no risk was noted with the other antibiotics.
Within the groups, there were 61 Tequin recipients with hypoglycemia and 86 with hyperglycemia. Overall, one of every 100 patients who took the drug was hospitalized.
The increased risks were similar in both groups of patients regardless of the previous presence or absence of diabetes.
"As compared with the use of other broad-spectrum oral antibiotics, including other fluoroquinolones," the study concluded, "the use of gatifloxacin among outpatients is associated with an increased risk of in-hospital treatment for both hypoglycemia and hyperglycemia."
The importance of these findings prompted the New England Journal of Medicine to make the study available online nearly a month in advance of its regular publication date of March 30, 2006. Changes in blood sugar levels can induce coma and other serious problems, including death.
The Mayo Clinic say patients taking Tequin need to be aware of the signs and symptoms of blood sugar fluctuations which include:
Confusion
Visual disturbances
Heart palpitations
Tremors
Frequent urination
Increased thirst
Dry mouth
In February 2006, Health Canada and the FDA issued advisory statements that said Bristol-Myers had told doctors that Tequin should not be used with diabetics, and that patients with kidney problems were more likely to experience serious side effects from the drug. The public health agencies also announced label changes for Tequin to include stronger warnings about the drug's link to blood-sugar related problems.
The editorial, "Serious Adverse Drug Effects - Seeing the Trees through the Forest," by Dr Jerry Gurwitz from the Meyers Primary Care Institute in Worcester, MA appears with the NEJM online study and says the FDA should consider mandating a "black-box" warning for Tequin's label or package insert.
"For every approved indication for [Tequin], there are safer, equally effective and less costly alternatives," Dr Gurwitz wrote in the editorial.
However, Dr David Juurlink, one of the Canadian researchers involved in the study, does not believe stronger warning labels are enough. He urges doctors not to prescribe Tequin at all.
"There are multiple alternatives," he says, "that are just as good and do not have this set of side effects that is unpredictable and potentially life threatening," according to the March 2, 2006 Wall Street Journal.
The actual number of blood-sugar risks are estimated to be much higher than listed in the study. Dr Juurlink was quoted by Reuters on March 1, 2006 as saying: "We can't identify everybody, only those who survived [a seizure from low blood sugar and made it] to the hospital or those sick enough to go to the hospital."
"If they died at home or in a pre-hospital setting, they would not have made it into the study," he said in the March 2, 2006 LA Times.
In the US, Tequin labeling has repeatedly changed over time based on other reports indicating that the antibiotic could dramatically alter blood sugar levels.
It came on the market in 1999, and by 2001, 3.3 million prescriptions per year were being written for the drug. Researchers began noticing problems that year, particularly alterations in glucose metabolism, according to the Times.
By 2003, 17 deaths had been linked to Tequin and prescriptions dropped to about 1.7 million per year.
One major contributor to that number, according to the Times, is the Department of Veterans Affairs, which added the drug to its formulary, designated an antibiotic of first choice, in part because Bristol-Myers offered the government a deal price of $1.35 per pill, verses the $8 to $10 per pill charged for Tequin and other fluoroquinolones at pharmacies, said Dr. Richard Frothingham of Duke University, according to the Times.
The government also chose Tequin because its risk of glucose abnormalities did not seem to be any higher than other antibiotics in the class, Dr Juurlink said. In light of the new findings, he told the Times, "the VA needs to very promptly revisit their policy."
Other adverse effects have also contributed to the withdrawal or restriction of several other drugs in this class of antibiotics including kidney failure and liver problems, according to the Mayo Clinic web site.
In addition, a wide range of neurological adverse effects linked to the fluoroquinolone antibiotics, reportedly found to occur in as many as 7% of patients, are described in a medical study conducted in 2001. These side effect symptoms include pins and needles, numbness, tingling, muscle and joint pain, palpitations, malaise, panic attacks, and anxiety, according to the study, "Peripheral Neuropathy Associated with Fluoroquinolones," by Jay S. Cohen, MD, in the December 2001, issue of The Annals of Pharmacotherapy, Volume 35.
Dr Cohen, President and Executive Director of the Center for the Prevention of Medication Side Effects, authored the study on long-term reactions to fluoroquinolones and the results were pre-released in October 2001, during the anthrax scare when Cipro was being widely prescribed without proper warnings to patients.
Within days of the publication, Dr Cohen says the CDC changed their guidelines and listed doxycycline and penicillin antibiotics as the preferred treatment for anthrax exposure before Cipro.
Doxycycline and penicillin were associated with much fewer serious side effects than fluoroquinolones, and were not linked to the disabling and long-term reactions identified in the study.
In most cases, he says side effects were multiple and involved many systems of the body.
The study found nervous system symptoms occurred in 91% of the patients, sensory system symptoms in 42%, musculoskeletal side effects in 73%, cardiovascular adverse effects in 36%, skin reactions in 29%, and gastrointestinal symptoms in 18% of the patients.
Dr Cohen found it especially alarming that severe reactions were occurring in patients who were young, healthy, and active, and most often were receiving antibiotic treatment for mild infections such as sinusitis, urinary or prostate infections. Most reactions occurred quickly, sometimes with just a few doses of the antibiotic.
For example, a male patient, age 36, previously in good health, ended up with chronic, debilitating multi-focal neuropathy, fibromyalgia, chronic fatigue, gastrointestinal problems, heart arrhythmia requiring pacemaker, carpal tunnel syndrome, chronic multiple joint pains, and chronic pain. Five years later at age 41, the patient was still disabled.
A previously healthy 32-year-old female patient was treated for a urinary infection and after 5 days, developed pain in wrists, neck, back, knees, hips, elbows, shoulders, and Achilles tendons.
A 34-year-old healthy male, was treated for a prostate infection and experienced side effects that included muscle spasms and twitching, numbness, impaired coordination, weakness, increased sensitivity to temperatures, fatigue, multiple joint, muscle pain, palpitations, and blurred vision for more than 1 year.
A 47-year-old female patient who was previously in good health, sought treatment for sinusitis and within 2 days of taking the antibiotic, developed severe joint pain in her hands, insomnia, severe agitation, weakness, dizziness, severe fatigue, mental infusion, abnormal dreams, and gastrointestinal symptoms, with many of the adverse effects listed as still severe after 7 months.
Another woman aged 49, with previous good health, received antibiotics for a pelvic infection that resulted in burning pain, memory loss, joint pains, palpitations, nerve pain, insomnia, abnormal sense of smell, tinnitis, and panic attacks for a duration of more than 3 years.
Another 35-year-old male, in good health, received treatment for a prostate infection and after one dose of medication he experienced ringing in the ears and peripheral nerve symptoms that lasted 2 weeks. He then developed tendonitis in his shoulders, elbows, wrists, hands, and Achilles tendons, with burning pain and tightness in his calves. This man was still unable to walk more than a short distance 2 months later.
"Prior to taking the medication I asked about side effects and was told there were none for adults except an upset stomach," this patient told Dr Cohen. "Afterwards I was told that what I was experiencing could not be related to the drug," he said.
Denying the link between the adverse events and the fluoroquinolones is apparently common. "In most cases," Dr Cohen says, "their doctors have dismissed their complaints or outright deny that the reactions could occur with fluoroquinolones."
"Yet extensive medical workups do not find any other cause," he reports.
"Worse, there are no known effective treatments," he says. "Thus, these people suffer pain and disability for weeks, months, years."
"Overall, my sense is that these reactions are not rare," Dr Cohen advises.
"Patients have a right of informed consent, and this includes warnings of potential serious, disabling reactions," he notes.
"Most of all," he warns, "we must educate doctors to avoid prescribing fluoroquinolones for minor infections, instead saving them for serious infections, just as we do with other groups of antibiotics with serious toxicities."
In the January 8, 2002 article titled, "Side Effects of Quinolone Antibiotics Like Tequin (Gatifloxacin) Can Be Serious," Mary Shomen gives a first-hand account of how varied and frightening some of the Tequin side effects can be.
Ms Shomen was prescribed Tequin for a sinus infection at an urgent care clinic and within one day experienced dizziness, tingling in her hands and knees, pain in her legs, and weakness in her arms and legs. A day later she says shortness of breath set in.
"I thought my symptoms might be related to my sinus infection," she wrote, "until I realized that they went away at night, and would start up again about an hour after taking my morning Tequin pill."
After four days Ms Shomen said, "I started having worsening shortening of breath, and difficulty swallowing, so I took two Beneadryl and called the doctor."
The call to the doctor resulted in a trip to the emergency room to see whether she was having a life-threatening allergic reaction to Tequin. At the hospital they discovered her airways were swollen so she was instructed to stay on Benadryl for 2 days.
"In the meantime," Ms Shomen recounts, "the tingling, numbness, difficulty swallowing and other neurological symptoms continued."
Four days later she says her memory was shot and she was still experiencing the tingling, numbness and dizziness. "After a night-time emergency call to my regular physician," she notes, "she suggested that I take some clonazepam (Klonopin), a mild tranquilizer, to see if that could calm down the overreactive nervous system."
The Klonopin calmed the symptoms and the doctor recommended that she remain on the drug until the side effects fully subsided.
"What I had was a dangerous - and even potentially life-threatening - drug reaction," Ms Shomen explains. "Who knows what might have happened had I not taken the Benadryl - an antihistimine - when the shortness of breath and airway constriction began?"
On March 1, 2006, Reuters reported that Bristol-Myers spokesman, Eric Miller said the company had decided to stop actively marketing Tequin, although his comments seemed to imply that the decision was based on economics rather than safety concerns.
Mr Miller noted that although Tequin was introduced onto the market in 1999, it only generated $150 million in sales for Bristol-Myers in 2005.
However, Bristol-Meyers choices related to the sale of Tequin may be limited. According to the editorial accompanying the study in the online NEJM. "It seems clear that the drug's place among broad-spectrum antibiotics available for outpatient use is tenuous at best."
Wednesday, July 28, 2010
The Holes in Bush's FDA
A Perpertual Leaker of Inside Dope
January 8, 2008 Evelyn Pringle
The steady leaking of insider information about products under review by the FDA has caused enormous losses for average American investors since the Bush Administration took control of the agency six years ago.
There are several ways that investors can profit from this type of insider information. The first is obvious, buy the stock because approval of a product will almost certainly raise a company's stock value. Investors who know about the decision ahead of time can bet the farm based on that information.
But investors who are tipped off that a product will not be approved can do the opposite. They can bet that company's stock value will fall by selling the stock short knowing full-well that the minute the news of non-approval becomes public, the stock's value will drop like a rock.
When the leaking of this type of information occurs, the losers are always the investors who play by the rules and make bets based on the best public information available. Unfortunately, in many instances, these are the very people who can least afford the loss.
One high-ranking member of the Bush Administration's FDA, Dr Richard Pazdur, has been one of the leakers in two cases involving cancer drugs that caused investors to lose vast amounts of money.
The first case devastated investors when a company's stock value dropped more than $1.5 billion in less than 3 weeks after Dr Pazdur tipped off the Cancer Leadership Council's legal counsel Samuel Turner that the FDA planned to reject the application for approval of a cancer drug the week before the decision was scheduled to be sent to the main sponsor, ImClone, on December 28, 2001.
At that time, Mr Turner also was a registered lobbyist for a number of pharmaceutical companies, including Bristol-Myers Squibb, which just happens to be the largest manufacturer of chemotherapeutic drugs.
Bristol-Meyer tipped off ImClone owners Harlan and Sam Waxal, and family members immediately started selling their stock. An investigation by the SEC later determined that the Waksals sold more than $10 million worth of stock in the 48 hours before the FDA's rejection of the application for drug was made public.
According to a June 16, 2002 report on Newsbytes News Network, short sellers also made millions by placing bets that ImClone's stock value would fall in the weeks before the FDA publicly rejected the application.
The House Committee on Energy and Commerce investigated the insider trading in this case, and a subcommittee held a hearing on June 13, 2002. At the start, the chairman noted that there were two stories here.
One, he said, "will be more fully told by the SEC and the Justice Department as it examines how the FDA process and what appears to be some rather amoristic players conspired in a way that allowed insider trading to potentially occur and an awful lot of investors to lose a lot of money while insiders were trading on information that was available only to them."
"The other story," he noted, "is about the process at FDA and how the FDA process allowed this to happen."
A transcript of the hearings shows that when members of Congress asked directly who within the FDA leaked the information to Bristol-Myers, Dr Pazdur and the rest of the Bush Administration officials talked in circles and never answered.
But in the end, somebody pulled some strings because Dr Pazdur got off Scott free, which probably accounts for his lack of fear when engaging in similar, behind-the-scenes activities in 2007.
In the more recent case, the continued short selling in Dendreon's stock following the Provenge Advisory Committee meeting of March 29, 2006, despite the fact that the Committee recommended approval of the drug, surely indicates that information leaked to Wall Street from inside the FDA guaranteed that the drug would not be approved.
On May 9, 2007, when Dendreon announced to the public that the FDA had issued the company a Complete Response Letter instead of an approval letter, the market value of Dendreon dropped more than 60% in one day.
The known people behind the "leaks" in this case are Dr Pazdur, along 2 members of the Advisory Committee who were chosen to participate on the panel by Dr Pazdur. When persons serve on these committees, they become "special government employees," and are subject to the same rules and regulations as all government employees.
When the Provenge Committee recommended approval, there were two votes taken. The first was on safety and the vote was 17-0 that the drug was safe. The second was on efficacy and the vote was 13-4 that the drug demonstrated "substantial evidence" of efficacy, the federally mandated standard.
The approval of this new cancer vaccine represented a grave threat to the multi-billion dollar chemotherapy industry. Dendreon is the first company to seek approval of a drug in a promising new class of immunotherapies that direct the body's own immune system to attack only cancer cells, unlike chemotherapy which destroys cancer cells but damages healthy cells and the immune system as well.
Provenge sought approval to treat men in the final stage of prostate cancer whose only option is months of chemotherapy with the drug Taxotere, which causes debilitating side effects and extends life on average 2.5 months.
In applying for approval, Dendreon submitted a study that showed 3 injections of Provenge extended life by nearly double that chemotherapy and the side effects, if any, consisted of flu-like symptoms for one or 2 days.
If the new immunotherapies turn out to be as effective as some experts claim, chemotherapy and radiation treatments could become obsolete in the not to distant future. Dr Pazdur knew this all too well. In fact, his fear was that if Provenge were to be approved, it would establish a new standard of care for late stage prostate cancer patients and from then on testing of new therapies would be up against Provenge.
He was also ticked off about the fact that the FDA had chosen the Center for Biologics Evaluation and Research to control the Provenge Advisory Committee instead of the Center for Drug Evaluation and Research, which he controlled.
So as a back-door means of regaining control, he recruited his two partners in crime, Dr Howard Scher, from the Memorial Sloan-Kettering Cancer Center, and Dr Maha Hussain, from Michigan University, to serve on the Advisory Committee to assist him in thwarting Dendreon's bid for the approval of Provenge.
Both of these doctors have made a fortune from their involvement in the cancer treatment and research racket over the past 2 decades. And they also stood to lose a fortune if the chemo-cartel was dismantled.
Investors had every reason to believe that Provenge would be approved once the Advisory Committee voted for approval. The FDA had never refused to follow a recommendation by its own experts to approve a drug for dying cancer patients who had no other options.
While testifying at the hearing, Dr David Penson, Associate Professor of Urology and Preventative Medicine at the University of Southern California, told the panel: "If you turn this drug down, it will likely set back the innovative field of active cellular immunotherapy in cancer many, many years."
He warned that the Committee's decision "will not only affect prostate cancer patients, but it may have an effect on the larger population of oncology patients in general."
Dr Hussain and Dr Scher were positioned on the panel to do everything in their power to make sure the vaccine was not approved. But their best efforts failed and within two weeks after the panel voted to approve the Provenge, Dendreon stock had nearly tripled in value and analysts were predicting that the vaccine could bring in $1 billion annually.
However, it was soon obvious that something was up, because the short sellers were still betting millions that the stock value would fall. On April 29, 2007, Bloomberg reported that shares were being sold short "at a record pace" as investors "bet the company's experimental prostate-cancer drug will fail to win approval from U.S. regulators."
All totalled, 33.9 million shares were sold short by the end of April. In hindsight, figuring out why people would engage in such risky betting was a no-brainer. The only people who could have known that Dendreon stock was headed for a nose-dive on May 9, 2007, because the FDA was going to overrule it's own panel by denying the approval of a cancer drug for dying patients for the first time in history, were the people who made it happen.
As late as May 7, 2007, Prohost Biotechnology, a firm that evaluates companies and publishes a monthly newsletter for investors, was calling Dendreon a good investment on its web site, stating: We Have A New Pick "DENDERON AGAIN."
The web site went on to explain why the firm was predicting that the short sellers were wrong in betting against the company, by stating in part:
This time, positive investors/analysts are determined to neutralize the shorters' efforts. Why not, if the verdict is expected in 10 days only and the committee, which was appointed by the FDA itself has already voted 17-0 in favor of safety and 13-4 in favor of efficacy?
We are with the approval, Prohost said. "As a matter of fact, we expect it on May 15, based on many facts, the most important is the result of the FDA committee's voting."
The firm noted that the experts on the panel would not have been chosen by the FDA if they were not highly regarded researchers, medical doctors, and academicians, and stated:
"If the results of voting would have been 50-50, we would have understood the need for the FDA to take a stand. But with a landslide voting in favor of approval, we do not see why the FDA should hesitate to follow the committee's recommendation of approval.
"Besides, the vaccine is safe. It acts synergistically with the available treatments and it helped desperate patients survive advanced prostate cancer."
But as it turns out, another plot was put in action immediately after the news came out that the panel recommended approval, in which government officials at the FDA and the National Cancer Institute worked with Dr Scher, and probably Dr Hussain, to compose letters with bogus reasons why the FDA should not follow the recommendation.
Once the rough drafts were edited, the letters were sent to the FDA by email and hardcopy, and leaked for publication on the internet by "The Cancer Letter," which just happens to be the same rag used to leak insider information in the ImClone case.
The overly dramatic Dr Scher, even went so far as to tell Thomas Fleming, another doctor who just happened to send a letter to the FDA, disparaging Provenge, which was also put out on the internet by "The Cancer Letter," that he could not sleep because he was so concerned over the possibility of patients being harmed if Provenge was approved and that's why he wrote the letter. Dr Fleming then noted that he could not sleep either.
This is an utterly ridiculous remark coming from Dr Scher, considering that he and Dr Hussain voted with the majority 17-0 that Provenge was safe at the hearing.
The pharmaceutical companies that stood to benefit the most from the non-approval of Provenge were Novacea, Schering-Plough and Sanofi-Aventis because they have billions of dollars invested in research, drug trials, and cancer treatments involving therapies that would compete directly with Provenge for the same late stage prostate cancer patients.
Dr Scher and Dr Hussain, as well as her husband, are involved in dozens of studies conducted by the same companies. Both Dr Scher and Dr Hussain are consultants and members of the scientific advisory board for Novacea, which produces Asentar together with Schering-Plough.
Asentar would directly compete with Provenge and at the time of the Advisory Committee hearing, Dr Scher was the co-lead investigator on trials of Asentar
According to www.portfolio.com, Dr Scher is also an officer, member of the Board of Directors, and a member of the Scientific Advisory Board of ProQuest Investments, which was had mega-bucks invested in Novacea during 2007. However, for some odd reason, ProQuest's web site no longer lists the names for the Scientific Advisory Board.
Dr Scher and Dr Hussain have also both received research funding from Sanofi-Aventis the maker of Taxotere.
A review of Dr Hussain's most current resume in fact, shows that she's been on one long global junket funded by the cancer treatment and research racket for close to 2 decades. She apparently began her journey in Bagdad, Iraq, in1980, and 2 years later she was in the UK and a year after that she ended up in Detroit, Michigan.
It looks like her home base has been Ann Arbor, Michigan since late 2002, that is in between her 6 trips to Canada, 3 to Hawaii, 3 to Puerto Rico, 2 to St Thomas, 2 to Barcelona, and at least 1 trip to Japan, China, Jordon, Lisbon, Monte Carlo, Bermuda, and Austria, in addition to her 17 trips to California, 9 to Chicago, 4 to New Orleans, 5 to New York, 9 to Florida, and at least 38 trips to other states.
The list of excursions certainly demonstrates that the good doctor enjoyed quite a lot of travel on someone else's dime. In fact, her hotel fees alone would put a bonifide hooker to shame.
Its impossible to determine the amount of "research" funding funneled her way because the amount is redacted for half of the grants listed. But at a bare minimum, she had at least 28 million "current" reasons to sabotage the approval of Provenge.
Under "Current Grant Support," she lists 11 grants, although 5 have no amounts. But the total for the other 6 comes to over $28 million, and she will be receiving income from a few of these grants for several more years.
Dr Hussain also lists another 2 grants as submitted, with all information redacted. She lists 5 under "Active Research," all involving treatments for late stage prostate cancer, but not one includes the amount. No dates are listed for these 5 grants either, which makes it impossible to estimate how long she intends to profit from this research.
The doctor also lists 30 funding sources under "Past", but only 6 have amounts. The total for those 6 comes to more than $20 million, so it would probably be safe to say that if all amounts were to be listed, Dr Hussain had at least 100 million good reasons to derail the approval of Provenge.
All the plotting by persons benefiting from the non-approval of Provenge might have gone undetected if not for the non-profit advocacy group, Care-To-Live. The group filed a lawsuit in Federal court against officials in charge of the FDA, including Dr Pazdur and Dr Scher, seeking an injunction to overturn the FDA's decision and to make Provenge available immediately to extend the lives of dying prostate cancer patients.
By filing the lawsuit, the group was able to gain access to a lot of information and after reading much of it, one thing's for sure, the government officials involved in this sick plot will never be accused of wasting time on the clock worrying about dying cancer victims.
Another case of leaking occurred on March 1, 2006, when the FDA sent a letter to the Canadian investment firm, Infinium Capital, that said the agency would allow testing for a generic version of Vancocin, marketed by ViroPharma, to be conducted in a test tube.
Two weeks later, after allowing plenty of time for persons with the inside information to position themselves to make a killing in the stock market, Infinium issued a report on ViroPharma stating, "Generics . . . sooner than you think".
According to an SEC filing by ViroPharma, Infinium's report was the first public disclosure of the new testing standard and:
"ViroPharma itself had not previously heard that OGD had lowered its BE standard for Vancocin. Nor it would seem, except those to whom OGD had privately communicated, had anyone else."
ViroPharma's filing went on to note that Infinium's report stated:
"Our recent communications with the FDA regarding the approval process for a potential generic competitor to Vancocin lead us to believe a generic could enter the market 1-2 years sooner than current expectations."
What "recent communications with FDA" might mean, the filing states, beyond the March 1, 2006 letter to Infinium, is unclear to ViroPharma. On March 16, 2006, Medindia.com dropped a bombshell when it informed the public of the news by quoting analysts at Infinium as saying it could mean a generic version would be available by early 2008.
"Previously, generic manufacturers may not have been interested in developing this therapeutic due to its low revenue potential; however, with the recent sales growth of 133 percent in 2005, Vancocin is now on the radar screen," an Infinium analyst told Medindia.
Infinium's announcement caused shares of ViroPharma "to dip by about 33 percent," according to Medindia. But in fact, Infinium's report triggered a multi-day stock sell-off that cut the company's market capitalization by 40%, or roughly $500,000,000.
The approval process prior to the FDA's unexpected announcement required trials to be conducted on humans. ViroPharma has filed a Petition to stop the approval of generic versions with allegations that the FDA violated the Freedom of Information Act, the Data Quality Act, the Administrative Procedure Act, and its own Standards of Conduct.
Vancocin is used to treat hospital-acquired bacterial infections in the lower gastrointestinal tract caused by the bacterium Clostridium difficile. In order to be effective, the drug must be released in one specific section of the intestines, making its release mechanism far more difficult to replicate than other drugs.
The release of an ineffective version of Vancocin at this point in time would be especially dangerous because recent studies have shown that cases of Clostridium difficile-associated disease (CDAD) are increasing world-world. The disease causes 400,000 cases of diarrhea and colitis each year in the US, according to the US Department of Veterans Affairs.
In addition, a paper by Michel Warney, et al., entitled, "Toxin Production by an Emerging Strain of Clostridium difficile Associated with Outbreaks of Severe Disease in North America and Europe," in the September 2005 Lancet medical journal, reported a new strain of C difficile that produces up to 23 times more toxins than previous strains; this strain has been implicated as the cause of a more severe form of the disease
A May 11, 2007, report by the Pennsylvania Health Care Cost Containment Council said that in 2005, patients with CDAD were hospitalized 2-and-a-half times longer, charged over twice as much, and were 4 times as likely to die as patients without the disease.
On average, the report notes, patients with CDAD remain in the hospital almost 7 days longer at a cost of $73,576, verses the average charge of $30,833 for patients without the disease. A November 2007 report entitled, "The Emerging Infectious Challenge of Clostridium difficile-Associated Disease in Massachusetts Hospitals: Clinical and Economic Consequences," cites a "conservative estimate" of the annual cost for CDAD management in the US as $3.2 billion.
People treated with antibiotics are at the highest risk because antibiotics disrupt the balance of bacteria in the GI tract, which allows C difficile bacteria to multiply. CDAD is highly infectious and can spread by contact with patients or touching surfaces contaminated with C difficile spores. The severity of the disease ranges from mild cases of diarrhea to painful colitis, bloodstream infections or death.
Years ago, CDAD was almost exclusively limited to patients in hospital or long-term care settings where infectious diseases spread easily. But there are now widespread reports of patients developing CDAD outside hospital settings, referred to as "community-acquired" CDAD, and with no antibiotic exposure.
Recent studies indicate that many cases may be caused by proton pump inhibitor drugs which inhibit the production of gastric acid in the stomach that acts as a defense against bacteria and spores, widely used by persons with ulcers and other GI illnesses.
The December 21, 2005, Journal of American Medical Association published a report by Canadian researchers based on studies that determined that gastric acid-suppressant drugs were associated with the rising cases of community-acquired CDAD.
The researchers used the United Kingdom General Practice Research Database and identified all 1,672 cases of CDAD recorded between 1994 and 2004 and found that 1,233, or 74%, of the patients had not been hospitalized in the year prior to the diagnosis and were considered community-acquired.
The study showed the increase in community-acquired cases rose from less than 1 per 100,000 in 1994 to 22 per 100,000 in 2004 and during this same period, prescriptions for antibiotics had decreased while prescriptions for proton pump inhibitors had increased.
The first course of treatment for CDAD caused by antibiotics is to stop the antibiotics. But if diarrhea continues and becomes severe, Vancocin is a treatment of last resort for very sick patients which means there is no room for error.
The FDA claims that dissolution testing for the generic version can be done by creating a test tube solution that replicates the environment in the lower intestine. But experts say it would be next to impossible to replicate the GI tracts of very ill and elderly patients to determine whether the generic version will work the same in the targeted area.
Experts also point out that drug interactions, such as those in patients on proton pump inhibitors would make it hard to develop a solution that would replicate the GI tract.
The approval of an ineffective generic version of Vancocin, will subject millions of people to potentially fatal risks because the patients who end up being treated with this medication will have no second chances if it fails.
The FDA is currently under attack for doing the exact same thing by not requiring adequate testing for the generic version of the antidepressant Wellbutrin. The FDA approved the generic in 2006 and after a steady stream of patients reported that they were experiencing serious side effects, testing by ConsumerLabs, revealed that the time release rate of the active ingredient was much faster than the release rate in the original drug.
The consumer-product testing group, ConsumerLab began investigating the drug after Joe and Terry Graedon, authors of The People's Pharmacy column, came to the group with complaints received from readers of their column. While the Graedons had received complaints about generic drugs before, "we had never received this volume of response," Joe Graedon, a pharmacologist, told MSNBC on October 12, 2007.
"In almost all cases people were saying their depression returned," he said. Users also complained about severe headaches, digestive problems, insomnia, anxiety, and tremors.
ConsumerLab performed dissolution testing on 6 samples of each medication and found that even though both contained the same amount of the active ingredient, the generic released nearly 50% of the ingredient in the first 4 hours verses 25% by Wellbutrin.
"It's been an eye-opener for everyone," ConsumerLab President, Dr Tod Cooperman, told MSNBC. "It makes you question whether generics are always going to be equivalent to the original product."
"If these things are releasing at such different rates," he advised, "it's hard to believe they'd be acting the same way in your body."
"It would seem very difficult to imagine that the results we saw would be acceptable results," Dr Cooperman told MSNBC.
He pointed out that the release of the active ingredient more quickly could mean there is less medication available to the patient later, and may explain why patients experienced a return of their depression.
He said a time-release problem might also explain why patients experienced more side effects, such as headache, irritability and nausea, if they received a high dose of the medicine upfront. "Too much Wellbutrin can cause side effects, even the potential for seizure," he told MSNBC.
The Canadian firm Biovial filed a petition with the FDA in 2005, asking the agency to require generic makers to conduct more rigorous testing of generic versions of Wellbutrin prior to their approval but apparently the agency ignored the request.
An agency spokesperson told MSNBC that the FDA does not require generic makers to do clinical trials on hundreds or thousands of people as required for name brand drugs. It only requires lab data and "bioequivalence" testing in about 24 to 36 healthy volunteers showing that the drug enters the bloodstream in a similar manner to the original product.
Since the generic version was approved, millions of consumers have switched to the drug to save money which means a high number of patients may be experiencing serious side effects without knowledge of the cause. Experts say this whole problem could have been avoided had testing on humans been conducted to check the release mechanism before millions of scripts were written.
"Sustained release mechanisms are not that easy to develop, and they tend to be proprietary in nature," Michael Katz, clinical associate professor of pharmacy practice and science at the University of Arizona College of Pharmacy told MSNBC.
"It would be difficult for a generic manufacturer to reproduce the same release characteristics as the brand-name product," he stated.
"Such differences clearly could have an impact on patients," he said, "and my view is that sustained-release products are among the relatively short list of products that should not be switched."
Experts say the time release characteristics would be even more difficult to replicate in a generic version of Vancocin, where the concern is not just about how much of the drug is released into the blood stream but rather in one specific section of the GI tract.
The leaking of information in the Vancocin case is reminiscent of a major scandal that erupted during the first Bush Administration in 1989, when FDA officials were charged with taking bribes from generic makers and sharing insider information.
On August 28, 1989, Time magazine reported that an investigation by the Justice Department had uncovered evidence that "some makers of generic pharmaceuticals falsified laboratory test results and paid off FDA chemists to gain quick Government approval for their products."
In that case, Charles Chang the head of the FDA's generic division and two co-workers pleaded guilty to accepting a total of $24,300 in illegal gifts in exchange for preferential treatment for certain generic makers in July 1989, according to the Time report.
In the end, the generic scandal during the first Bush Administration landed Mr Chang in federal prison and caused 42 others and 10 companies to be convicted on charges of fraud and corruption and the FDA Commissioner Frank Young resigned in November 1989.
The crooks in the current Bush Administration's FDA deserve the same fate.
January 8, 2008 Evelyn Pringle
The steady leaking of insider information about products under review by the FDA has caused enormous losses for average American investors since the Bush Administration took control of the agency six years ago.
There are several ways that investors can profit from this type of insider information. The first is obvious, buy the stock because approval of a product will almost certainly raise a company's stock value. Investors who know about the decision ahead of time can bet the farm based on that information.
But investors who are tipped off that a product will not be approved can do the opposite. They can bet that company's stock value will fall by selling the stock short knowing full-well that the minute the news of non-approval becomes public, the stock's value will drop like a rock.
When the leaking of this type of information occurs, the losers are always the investors who play by the rules and make bets based on the best public information available. Unfortunately, in many instances, these are the very people who can least afford the loss.
One high-ranking member of the Bush Administration's FDA, Dr Richard Pazdur, has been one of the leakers in two cases involving cancer drugs that caused investors to lose vast amounts of money.
The first case devastated investors when a company's stock value dropped more than $1.5 billion in less than 3 weeks after Dr Pazdur tipped off the Cancer Leadership Council's legal counsel Samuel Turner that the FDA planned to reject the application for approval of a cancer drug the week before the decision was scheduled to be sent to the main sponsor, ImClone, on December 28, 2001.
At that time, Mr Turner also was a registered lobbyist for a number of pharmaceutical companies, including Bristol-Myers Squibb, which just happens to be the largest manufacturer of chemotherapeutic drugs.
Bristol-Meyer tipped off ImClone owners Harlan and Sam Waxal, and family members immediately started selling their stock. An investigation by the SEC later determined that the Waksals sold more than $10 million worth of stock in the 48 hours before the FDA's rejection of the application for drug was made public.
According to a June 16, 2002 report on Newsbytes News Network, short sellers also made millions by placing bets that ImClone's stock value would fall in the weeks before the FDA publicly rejected the application.
The House Committee on Energy and Commerce investigated the insider trading in this case, and a subcommittee held a hearing on June 13, 2002. At the start, the chairman noted that there were two stories here.
One, he said, "will be more fully told by the SEC and the Justice Department as it examines how the FDA process and what appears to be some rather amoristic players conspired in a way that allowed insider trading to potentially occur and an awful lot of investors to lose a lot of money while insiders were trading on information that was available only to them."
"The other story," he noted, "is about the process at FDA and how the FDA process allowed this to happen."
A transcript of the hearings shows that when members of Congress asked directly who within the FDA leaked the information to Bristol-Myers, Dr Pazdur and the rest of the Bush Administration officials talked in circles and never answered.
But in the end, somebody pulled some strings because Dr Pazdur got off Scott free, which probably accounts for his lack of fear when engaging in similar, behind-the-scenes activities in 2007.
In the more recent case, the continued short selling in Dendreon's stock following the Provenge Advisory Committee meeting of March 29, 2006, despite the fact that the Committee recommended approval of the drug, surely indicates that information leaked to Wall Street from inside the FDA guaranteed that the drug would not be approved.
On May 9, 2007, when Dendreon announced to the public that the FDA had issued the company a Complete Response Letter instead of an approval letter, the market value of Dendreon dropped more than 60% in one day.
The known people behind the "leaks" in this case are Dr Pazdur, along 2 members of the Advisory Committee who were chosen to participate on the panel by Dr Pazdur. When persons serve on these committees, they become "special government employees," and are subject to the same rules and regulations as all government employees.
When the Provenge Committee recommended approval, there were two votes taken. The first was on safety and the vote was 17-0 that the drug was safe. The second was on efficacy and the vote was 13-4 that the drug demonstrated "substantial evidence" of efficacy, the federally mandated standard.
The approval of this new cancer vaccine represented a grave threat to the multi-billion dollar chemotherapy industry. Dendreon is the first company to seek approval of a drug in a promising new class of immunotherapies that direct the body's own immune system to attack only cancer cells, unlike chemotherapy which destroys cancer cells but damages healthy cells and the immune system as well.
Provenge sought approval to treat men in the final stage of prostate cancer whose only option is months of chemotherapy with the drug Taxotere, which causes debilitating side effects and extends life on average 2.5 months.
In applying for approval, Dendreon submitted a study that showed 3 injections of Provenge extended life by nearly double that chemotherapy and the side effects, if any, consisted of flu-like symptoms for one or 2 days.
If the new immunotherapies turn out to be as effective as some experts claim, chemotherapy and radiation treatments could become obsolete in the not to distant future. Dr Pazdur knew this all too well. In fact, his fear was that if Provenge were to be approved, it would establish a new standard of care for late stage prostate cancer patients and from then on testing of new therapies would be up against Provenge.
He was also ticked off about the fact that the FDA had chosen the Center for Biologics Evaluation and Research to control the Provenge Advisory Committee instead of the Center for Drug Evaluation and Research, which he controlled.
So as a back-door means of regaining control, he recruited his two partners in crime, Dr Howard Scher, from the Memorial Sloan-Kettering Cancer Center, and Dr Maha Hussain, from Michigan University, to serve on the Advisory Committee to assist him in thwarting Dendreon's bid for the approval of Provenge.
Both of these doctors have made a fortune from their involvement in the cancer treatment and research racket over the past 2 decades. And they also stood to lose a fortune if the chemo-cartel was dismantled.
Investors had every reason to believe that Provenge would be approved once the Advisory Committee voted for approval. The FDA had never refused to follow a recommendation by its own experts to approve a drug for dying cancer patients who had no other options.
While testifying at the hearing, Dr David Penson, Associate Professor of Urology and Preventative Medicine at the University of Southern California, told the panel: "If you turn this drug down, it will likely set back the innovative field of active cellular immunotherapy in cancer many, many years."
He warned that the Committee's decision "will not only affect prostate cancer patients, but it may have an effect on the larger population of oncology patients in general."
Dr Hussain and Dr Scher were positioned on the panel to do everything in their power to make sure the vaccine was not approved. But their best efforts failed and within two weeks after the panel voted to approve the Provenge, Dendreon stock had nearly tripled in value and analysts were predicting that the vaccine could bring in $1 billion annually.
However, it was soon obvious that something was up, because the short sellers were still betting millions that the stock value would fall. On April 29, 2007, Bloomberg reported that shares were being sold short "at a record pace" as investors "bet the company's experimental prostate-cancer drug will fail to win approval from U.S. regulators."
All totalled, 33.9 million shares were sold short by the end of April. In hindsight, figuring out why people would engage in such risky betting was a no-brainer. The only people who could have known that Dendreon stock was headed for a nose-dive on May 9, 2007, because the FDA was going to overrule it's own panel by denying the approval of a cancer drug for dying patients for the first time in history, were the people who made it happen.
As late as May 7, 2007, Prohost Biotechnology, a firm that evaluates companies and publishes a monthly newsletter for investors, was calling Dendreon a good investment on its web site, stating: We Have A New Pick "DENDERON AGAIN."
The web site went on to explain why the firm was predicting that the short sellers were wrong in betting against the company, by stating in part:
This time, positive investors/analysts are determined to neutralize the shorters' efforts. Why not, if the verdict is expected in 10 days only and the committee, which was appointed by the FDA itself has already voted 17-0 in favor of safety and 13-4 in favor of efficacy?
We are with the approval, Prohost said. "As a matter of fact, we expect it on May 15, based on many facts, the most important is the result of the FDA committee's voting."
The firm noted that the experts on the panel would not have been chosen by the FDA if they were not highly regarded researchers, medical doctors, and academicians, and stated:
"If the results of voting would have been 50-50, we would have understood the need for the FDA to take a stand. But with a landslide voting in favor of approval, we do not see why the FDA should hesitate to follow the committee's recommendation of approval.
"Besides, the vaccine is safe. It acts synergistically with the available treatments and it helped desperate patients survive advanced prostate cancer."
But as it turns out, another plot was put in action immediately after the news came out that the panel recommended approval, in which government officials at the FDA and the National Cancer Institute worked with Dr Scher, and probably Dr Hussain, to compose letters with bogus reasons why the FDA should not follow the recommendation.
Once the rough drafts were edited, the letters were sent to the FDA by email and hardcopy, and leaked for publication on the internet by "The Cancer Letter," which just happens to be the same rag used to leak insider information in the ImClone case.
The overly dramatic Dr Scher, even went so far as to tell Thomas Fleming, another doctor who just happened to send a letter to the FDA, disparaging Provenge, which was also put out on the internet by "The Cancer Letter," that he could not sleep because he was so concerned over the possibility of patients being harmed if Provenge was approved and that's why he wrote the letter. Dr Fleming then noted that he could not sleep either.
This is an utterly ridiculous remark coming from Dr Scher, considering that he and Dr Hussain voted with the majority 17-0 that Provenge was safe at the hearing.
The pharmaceutical companies that stood to benefit the most from the non-approval of Provenge were Novacea, Schering-Plough and Sanofi-Aventis because they have billions of dollars invested in research, drug trials, and cancer treatments involving therapies that would compete directly with Provenge for the same late stage prostate cancer patients.
Dr Scher and Dr Hussain, as well as her husband, are involved in dozens of studies conducted by the same companies. Both Dr Scher and Dr Hussain are consultants and members of the scientific advisory board for Novacea, which produces Asentar together with Schering-Plough.
Asentar would directly compete with Provenge and at the time of the Advisory Committee hearing, Dr Scher was the co-lead investigator on trials of Asentar
According to www.portfolio.com, Dr Scher is also an officer, member of the Board of Directors, and a member of the Scientific Advisory Board of ProQuest Investments, which was had mega-bucks invested in Novacea during 2007. However, for some odd reason, ProQuest's web site no longer lists the names for the Scientific Advisory Board.
Dr Scher and Dr Hussain have also both received research funding from Sanofi-Aventis the maker of Taxotere.
A review of Dr Hussain's most current resume in fact, shows that she's been on one long global junket funded by the cancer treatment and research racket for close to 2 decades. She apparently began her journey in Bagdad, Iraq, in1980, and 2 years later she was in the UK and a year after that she ended up in Detroit, Michigan.
It looks like her home base has been Ann Arbor, Michigan since late 2002, that is in between her 6 trips to Canada, 3 to Hawaii, 3 to Puerto Rico, 2 to St Thomas, 2 to Barcelona, and at least 1 trip to Japan, China, Jordon, Lisbon, Monte Carlo, Bermuda, and Austria, in addition to her 17 trips to California, 9 to Chicago, 4 to New Orleans, 5 to New York, 9 to Florida, and at least 38 trips to other states.
The list of excursions certainly demonstrates that the good doctor enjoyed quite a lot of travel on someone else's dime. In fact, her hotel fees alone would put a bonifide hooker to shame.
Its impossible to determine the amount of "research" funding funneled her way because the amount is redacted for half of the grants listed. But at a bare minimum, she had at least 28 million "current" reasons to sabotage the approval of Provenge.
Under "Current Grant Support," she lists 11 grants, although 5 have no amounts. But the total for the other 6 comes to over $28 million, and she will be receiving income from a few of these grants for several more years.
Dr Hussain also lists another 2 grants as submitted, with all information redacted. She lists 5 under "Active Research," all involving treatments for late stage prostate cancer, but not one includes the amount. No dates are listed for these 5 grants either, which makes it impossible to estimate how long she intends to profit from this research.
The doctor also lists 30 funding sources under "Past", but only 6 have amounts. The total for those 6 comes to more than $20 million, so it would probably be safe to say that if all amounts were to be listed, Dr Hussain had at least 100 million good reasons to derail the approval of Provenge.
All the plotting by persons benefiting from the non-approval of Provenge might have gone undetected if not for the non-profit advocacy group, Care-To-Live. The group filed a lawsuit in Federal court against officials in charge of the FDA, including Dr Pazdur and Dr Scher, seeking an injunction to overturn the FDA's decision and to make Provenge available immediately to extend the lives of dying prostate cancer patients.
By filing the lawsuit, the group was able to gain access to a lot of information and after reading much of it, one thing's for sure, the government officials involved in this sick plot will never be accused of wasting time on the clock worrying about dying cancer victims.
Another case of leaking occurred on March 1, 2006, when the FDA sent a letter to the Canadian investment firm, Infinium Capital, that said the agency would allow testing for a generic version of Vancocin, marketed by ViroPharma, to be conducted in a test tube.
Two weeks later, after allowing plenty of time for persons with the inside information to position themselves to make a killing in the stock market, Infinium issued a report on ViroPharma stating, "Generics . . . sooner than you think".
According to an SEC filing by ViroPharma, Infinium's report was the first public disclosure of the new testing standard and:
"ViroPharma itself had not previously heard that OGD had lowered its BE standard for Vancocin. Nor it would seem, except those to whom OGD had privately communicated, had anyone else."
ViroPharma's filing went on to note that Infinium's report stated:
"Our recent communications with the FDA regarding the approval process for a potential generic competitor to Vancocin lead us to believe a generic could enter the market 1-2 years sooner than current expectations."
What "recent communications with FDA" might mean, the filing states, beyond the March 1, 2006 letter to Infinium, is unclear to ViroPharma. On March 16, 2006, Medindia.com dropped a bombshell when it informed the public of the news by quoting analysts at Infinium as saying it could mean a generic version would be available by early 2008.
"Previously, generic manufacturers may not have been interested in developing this therapeutic due to its low revenue potential; however, with the recent sales growth of 133 percent in 2005, Vancocin is now on the radar screen," an Infinium analyst told Medindia.
Infinium's announcement caused shares of ViroPharma "to dip by about 33 percent," according to Medindia. But in fact, Infinium's report triggered a multi-day stock sell-off that cut the company's market capitalization by 40%, or roughly $500,000,000.
The approval process prior to the FDA's unexpected announcement required trials to be conducted on humans. ViroPharma has filed a Petition to stop the approval of generic versions with allegations that the FDA violated the Freedom of Information Act, the Data Quality Act, the Administrative Procedure Act, and its own Standards of Conduct.
Vancocin is used to treat hospital-acquired bacterial infections in the lower gastrointestinal tract caused by the bacterium Clostridium difficile. In order to be effective, the drug must be released in one specific section of the intestines, making its release mechanism far more difficult to replicate than other drugs.
The release of an ineffective version of Vancocin at this point in time would be especially dangerous because recent studies have shown that cases of Clostridium difficile-associated disease (CDAD) are increasing world-world. The disease causes 400,000 cases of diarrhea and colitis each year in the US, according to the US Department of Veterans Affairs.
In addition, a paper by Michel Warney, et al., entitled, "Toxin Production by an Emerging Strain of Clostridium difficile Associated with Outbreaks of Severe Disease in North America and Europe," in the September 2005 Lancet medical journal, reported a new strain of C difficile that produces up to 23 times more toxins than previous strains; this strain has been implicated as the cause of a more severe form of the disease
A May 11, 2007, report by the Pennsylvania Health Care Cost Containment Council said that in 2005, patients with CDAD were hospitalized 2-and-a-half times longer, charged over twice as much, and were 4 times as likely to die as patients without the disease.
On average, the report notes, patients with CDAD remain in the hospital almost 7 days longer at a cost of $73,576, verses the average charge of $30,833 for patients without the disease. A November 2007 report entitled, "The Emerging Infectious Challenge of Clostridium difficile-Associated Disease in Massachusetts Hospitals: Clinical and Economic Consequences," cites a "conservative estimate" of the annual cost for CDAD management in the US as $3.2 billion.
People treated with antibiotics are at the highest risk because antibiotics disrupt the balance of bacteria in the GI tract, which allows C difficile bacteria to multiply. CDAD is highly infectious and can spread by contact with patients or touching surfaces contaminated with C difficile spores. The severity of the disease ranges from mild cases of diarrhea to painful colitis, bloodstream infections or death.
Years ago, CDAD was almost exclusively limited to patients in hospital or long-term care settings where infectious diseases spread easily. But there are now widespread reports of patients developing CDAD outside hospital settings, referred to as "community-acquired" CDAD, and with no antibiotic exposure.
Recent studies indicate that many cases may be caused by proton pump inhibitor drugs which inhibit the production of gastric acid in the stomach that acts as a defense against bacteria and spores, widely used by persons with ulcers and other GI illnesses.
The December 21, 2005, Journal of American Medical Association published a report by Canadian researchers based on studies that determined that gastric acid-suppressant drugs were associated with the rising cases of community-acquired CDAD.
The researchers used the United Kingdom General Practice Research Database and identified all 1,672 cases of CDAD recorded between 1994 and 2004 and found that 1,233, or 74%, of the patients had not been hospitalized in the year prior to the diagnosis and were considered community-acquired.
The study showed the increase in community-acquired cases rose from less than 1 per 100,000 in 1994 to 22 per 100,000 in 2004 and during this same period, prescriptions for antibiotics had decreased while prescriptions for proton pump inhibitors had increased.
The first course of treatment for CDAD caused by antibiotics is to stop the antibiotics. But if diarrhea continues and becomes severe, Vancocin is a treatment of last resort for very sick patients which means there is no room for error.
The FDA claims that dissolution testing for the generic version can be done by creating a test tube solution that replicates the environment in the lower intestine. But experts say it would be next to impossible to replicate the GI tracts of very ill and elderly patients to determine whether the generic version will work the same in the targeted area.
Experts also point out that drug interactions, such as those in patients on proton pump inhibitors would make it hard to develop a solution that would replicate the GI tract.
The approval of an ineffective generic version of Vancocin, will subject millions of people to potentially fatal risks because the patients who end up being treated with this medication will have no second chances if it fails.
The FDA is currently under attack for doing the exact same thing by not requiring adequate testing for the generic version of the antidepressant Wellbutrin. The FDA approved the generic in 2006 and after a steady stream of patients reported that they were experiencing serious side effects, testing by ConsumerLabs, revealed that the time release rate of the active ingredient was much faster than the release rate in the original drug.
The consumer-product testing group, ConsumerLab began investigating the drug after Joe and Terry Graedon, authors of The People's Pharmacy column, came to the group with complaints received from readers of their column. While the Graedons had received complaints about generic drugs before, "we had never received this volume of response," Joe Graedon, a pharmacologist, told MSNBC on October 12, 2007.
"In almost all cases people were saying their depression returned," he said. Users also complained about severe headaches, digestive problems, insomnia, anxiety, and tremors.
ConsumerLab performed dissolution testing on 6 samples of each medication and found that even though both contained the same amount of the active ingredient, the generic released nearly 50% of the ingredient in the first 4 hours verses 25% by Wellbutrin.
"It's been an eye-opener for everyone," ConsumerLab President, Dr Tod Cooperman, told MSNBC. "It makes you question whether generics are always going to be equivalent to the original product."
"If these things are releasing at such different rates," he advised, "it's hard to believe they'd be acting the same way in your body."
"It would seem very difficult to imagine that the results we saw would be acceptable results," Dr Cooperman told MSNBC.
He pointed out that the release of the active ingredient more quickly could mean there is less medication available to the patient later, and may explain why patients experienced a return of their depression.
He said a time-release problem might also explain why patients experienced more side effects, such as headache, irritability and nausea, if they received a high dose of the medicine upfront. "Too much Wellbutrin can cause side effects, even the potential for seizure," he told MSNBC.
The Canadian firm Biovial filed a petition with the FDA in 2005, asking the agency to require generic makers to conduct more rigorous testing of generic versions of Wellbutrin prior to their approval but apparently the agency ignored the request.
An agency spokesperson told MSNBC that the FDA does not require generic makers to do clinical trials on hundreds or thousands of people as required for name brand drugs. It only requires lab data and "bioequivalence" testing in about 24 to 36 healthy volunteers showing that the drug enters the bloodstream in a similar manner to the original product.
Since the generic version was approved, millions of consumers have switched to the drug to save money which means a high number of patients may be experiencing serious side effects without knowledge of the cause. Experts say this whole problem could have been avoided had testing on humans been conducted to check the release mechanism before millions of scripts were written.
"Sustained release mechanisms are not that easy to develop, and they tend to be proprietary in nature," Michael Katz, clinical associate professor of pharmacy practice and science at the University of Arizona College of Pharmacy told MSNBC.
"It would be difficult for a generic manufacturer to reproduce the same release characteristics as the brand-name product," he stated.
"Such differences clearly could have an impact on patients," he said, "and my view is that sustained-release products are among the relatively short list of products that should not be switched."
Experts say the time release characteristics would be even more difficult to replicate in a generic version of Vancocin, where the concern is not just about how much of the drug is released into the blood stream but rather in one specific section of the GI tract.
The leaking of information in the Vancocin case is reminiscent of a major scandal that erupted during the first Bush Administration in 1989, when FDA officials were charged with taking bribes from generic makers and sharing insider information.
On August 28, 1989, Time magazine reported that an investigation by the Justice Department had uncovered evidence that "some makers of generic pharmaceuticals falsified laboratory test results and paid off FDA chemists to gain quick Government approval for their products."
In that case, Charles Chang the head of the FDA's generic division and two co-workers pleaded guilty to accepting a total of $24,300 in illegal gifts in exchange for preferential treatment for certain generic makers in July 1989, according to the Time report.
In the end, the generic scandal during the first Bush Administration landed Mr Chang in federal prison and caused 42 others and 10 companies to be convicted on charges of fraud and corruption and the FDA Commissioner Frank Young resigned in November 1989.
The crooks in the current Bush Administration's FDA deserve the same fate.
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