Tegretol's possible side effects from Webmed.comIf you experience any of the following serious side effects, contact your doctor immediately or seek emergency medical attention:
·an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives);
·liver damage (yellowing of the skin or eyes, nausea, abdominal pain or discomfort, severe fatigue);
·chest pain, high blood pressure (headache, flushing), or congestive heart failure (shortness of breath, swelling of ankles);
·numbness or tingling in the hands, feet, arms, or legs;
·body or muscle jerks;
·confusion, slurred speech, or fainting;
·continuing headache, hallucinations, or depression;
·severe nausea or vomiting;
·back-and-forth movements of the eyes;
·blurred or double vision; or
·decreased urination.
• Rarely, carbamazepine may cause serious blood problems. Notify your doctor immediately if you develop any of the following symptoms, which may be early signs of potential blood problems: fever, sore throat, rash, sores in the mouth, easy bruising, or red or purple bruising.
• Other, less serious side effects may be more likely to occur. Continue to take carbamazepine and talk to your doctor if you experience
·mild nausea, vomiting, diarrhea, constipation, or decreased appetite;
·dry mouth;
·joint or muscle aches or pains.
• Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.
If you experience any of the following serious side effects, contact your doctor immediately or seek emergency medical attention:
·an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives);
·liver damage (yellowing of the skin or eyes, nausea, abdominal pain or discomfort, severe fatigue);
·chest pain, high blood pressure (headache, flushing), or congestive heart failure (shortness of breath, swelling of ankles);
·numbness or tingling in the hands, feet, arms, or legs;
·body or muscle jerks;
·confusion, slurred speech, or fainting;
·continuing headache, hallucinations, or depression;
·severe nausea or vomiting;
·back-and-forth movements of the eyes;
·blurred or double vision; or
·decreased urination.
• Rarely, carbamazepine may cause serious blood problems. Notify your doctor immediately if you develop any of the following symptoms, which may be early signs of potential blood problems: fever, sore throat, rash, sores in the mouth, easy bruising, or red or purple bruising.
• Other, less serious side effects may be more likely to occur. Continue to take carbamazepine and talk to your doctor if you experience
·mild nausea, vomiting, diarrhea, constipation, or decreased appetite;
·dry mouth;
·joint or muscle aches or pains.
• Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.
"More children dying of drug side-effects"
(Western Morning News 28/11/02)
The number of suspected fatal side effects from drugs prescribed to children and reported by doctors has risen in the past decade, a new study revealed yesterday. The researchers found that anti-epileptic drugs were linked with the highest number of reported deaths and, in particular, liver damage. But the authors stressed that the overall benefit to children was likely to be far greater than the risk.
The study, published in the journal Archives of Disease in Childhood, looked at all suspected and fatal drug side effects in children and reported by doctors to the UK Medicines Control Agency (MCA) through its voluntary Yellow Card Scheme between 1964 and 2000. Vaccines and overdoses were excluded and no attempt was made to formally assess the cause of a child's death.
During this period 331 children aged up to 16 died and 390 suspect medicines were reported to the MCA. Altogether, almost half of the deaths occurred since 1991.
WHAT DOCTORS DON’T TELL YOU - E-NEWS BROADCAST No. 62 - 11 December 03
THE DRUGS DON'T WORK: And for once it's not us saying it, it's Glaxo
In an extraordinary admission, a senior executive with UK drug giant GlaxoSmithKline (GSK) has 'confessed' that the vast majority of prescription drugs don't work. Dr Allen Roses, worldwide vice-president of genetics at GSK, has told a conference that over 90 per cent of all drugs work for only between 30 per cent and 50 per cent of patients.
At the very bottom of the efficacy table are the cancer drugs, which work on only 25 per cent of patients. These are closely followed by Alzheimer's drugs that work on just 30 per cent of people. Drugs for rheumatoid arthritis, migraine, incontinence, hepatitis C, and diabetes work on only half the patients, at best. The most effective drugs are the analgesics, which work for to 80 per cent of those who take them.
This frank admission is also a very shocking one, and for several reasons. The pharmaceutical industry is about the most profitable in the world, and its profits are generated by drugs that everyone has implicitly believed would work (everyone apart from regular E-news readers, that is). Worse, in this scramble for profits, around 105,000 Americans and 40,000 Britons die every year from an adverse reaction to a drug, and many thousands more are permanently harmed from one.
Almost as astonishing has been the reaction from some of Roses's industry colleagues. "What he is saying will surprise the public but not his colleagues," said one industry scientist. Surprised may be a slight under-statement for the reaction of families who have lost a member to a drug-and one that the manufacturer probably knew would not work.
So it's no surprise to the drug companies. Is it a surprise, perhaps, to the drug regulators? Did they know that they were part of a scam? Or the government, maybe, that buys £7.2bn of drugs each year for the National Health Service? Are they also aware that at least two-thirds of that enormous expenditure is an utter waste?
How about the doctors? They are writing millions of prescriptions a year. Did they notice that their patients just weren't getting any better? Some commentators have described Roses's admission as a Ratner-like gaffe. For non-UK readers and those too young to remember, Gerald Ratner ran the UK's largest jewelers - until the day he 'joked' that his products were 'crap'.
But this was no Ratner moment. Roses knew full well what he was doing, and he almost certainly had his statement cleared by the very top executives at Glaxo. Roses has been described as a highly intelligent man, and he's certainly too smart to commit corporate suicide.
Roses is staking a major claim for his own division, into which Glaxo has poured billions of dollars of research money. Our guess is that Glaxo has taken the lead in the market, and will soon be launching a new approach to therapy, based on the patient's genetic make-up. In this new treatment model, patients will first be tested to discover the effectiveness of a drug, and if they are among the 20 per cent for whom the drug will work.
By allowing Roses to blow the whistle, Glaxo is playing a very high-risk game. Genetic profiling may be achievable, but it will cut drugs production by up to 80 per cent, so eating into profits. It may also not be a workable option, especially for an already overstretched health service. What then? We are just left with the information that most drugs don't work. Which is pretty much where we at WDDTY came in.
* Following on from Dr Roses's admission, you really must read the WDDTY book Secrets of the Drugs Industry. It lifts the lid on the drugs that don't work, those that are dangerous, and how the drugs industry masks its aggressive sales drives with supposed science. To order your copy, click on this link: http://www.wddty.co.uk/shop/details.asp?product=341
Her body burned by drug, not fire18-year-old has severe reaction to prescription
09:59 AM MST on Tuesday, May 4, 2004
By Carla McClain / Arizona Daily Star
A beautiful 18-year-old Tucson softball player has suffered severe burns over 80 percent of her body but has been nowhere near a fire. In an extremely rare, often fatal and little-known severe toxic reaction to a medical drug, Samantha Grasham's body caught fire - from the inside out - blistering most of her skin, as well as her mouth, throat, esophagus and airway, perhaps leaving her scarred for life. She spent nearly three weeks in the Burn Unit at St. Mary's Hospital, as doctors there worked to save her life and her skin.
As happens in most of these strange cases of what is known as Stevens-Johnson syndrome, there was no warning that Grasham would react so severely to a medication. Most people never know they are at risk, and doctors often do not recognize the syndrome when they see it. Yet many common drugs - including prescription painkillers and antibiotics - even over-the-counter pain and fever medicines for children - are linked to this "fire in the flesh."
In the worst cases, people are not only scarred, but also blinded and dependent on breathing and feeding tubes - if they survive. In its severe form, when the skin is literally burned off the body and even internal organs are damaged, about half die. The U.S. Food & Drug Administration has issued dozens of warnings about drugs that can trigger Stevens-Johnson syndrome (SJS) - including the one given to Grasham - but the warnings receive little publicity.
"I think it is commonly misdiagnosed, especially in the early stages," said Dr. Norman Levine, longtime University of Arizona dermatologist, who sees about one case a year. "But a physician will seldom miss it in a very sick patient, once it has severely progressed. When that happens, it can be devastating." Although the syndrome is rare - occurring at the rate of about 1 to 7 cases per million people per year - some say it is starting to increase significantly as more antibiotics and anti-inflammatory drugs hit the market. "The problem is that the drugs causing this syndrome are unbelievably common - things like ibuprofen, that people take every day," said Levine. "Something in the drug leads to a very inappropriate, wildly inflammatory immune response that causes the skin to die.
"It's completely unpredictable. Someone can be taking a drug safely for years, then all of a sudden have a horrible reaction to it. Those who get it are not highly allergic. This is just plain bad luck." In the case of Samantha Grasham, the syndrome stopped her life cold, ending her athletic scholarship, her education, her life plans. "I was always so active and involved - in sport and games. I loved college, and traveling," she said. "Now there is nothing - just these scars all over my body." Like many victims, she now battles chronic fatigue. The former softball star at Desert View High School entered El Paso Community College in Texas last fall on a two-year athletic scholarship. But in early January, during the first day of softball practice, she had an unexpected, one-time seizure that caused her to fall and black out.
After a series of tests back home in Tucson, Grasham was placed on an anti-seizure drug, Lamictal, by a neurologist, who told her she could return to school and go on with her life normally. She did, but about 10 days after starting the drug, she noticed a small rash on her arm. Though she played first base in a softball game the next day, the rash by then had spread to her arms, legs, back and face. With the rash worsening by the hour, now itching and burning, her ears and mouth starting to blister, Grasham went to urgent care in El Paso. A doctor there correctly diagnosed an allergic reaction to the drug she was taking but never told her to stop taking it - the first terrible mistake. After getting an allergy medicine, she was sent home.
Two days later, "my face was on fire," as Grasham describes it, and the burns were moving down her airway, interfering with her breathing. She went back to urgent care, where again no one told her to stop the drug. Instead they gave her another drug, prednisone, also linked to cases of Stevens-Johnson syndrome. The next day, her whole body now blistering and burning, her face completely inflamed, Grasham's family made an emergency trip to El Paso. "Oh my God, I couldn't even speak when I saw her. I couldn't even cry - I was so shocked," said her mother, Patricia Grasham. "Her mouth was one big blister; her face was all red and swollen. Her eyes were burning so bad we had to keep wet towels on them all the way home. The blisters were all over her mouth and down her throat. She was drooling, and in so much pain."
Driving straight to the emergency room at Tucson Medical Center, the family finally found out what had attacked their daughter. An emergency physician immediately diagnosed Stevens-Johnson syndrome and nailed Lamictal as the likely cause. Grasham remembers many doctors and nurses coming into her room to see this highly unusual and bizarre eruption, many of them for the first time. "Once you see the mucous membranes blistering, and you get a history of how this progressed in the patient, an emergency physician should know what they're looking at," said Dr. Ron Widman, chief of emergency services at TMC.
"But this is not very common, so yes, certainly, we want our young doctors to see it." Although Grasham was finally off Lamictal, the syndrome kept worsening - possibly fueled by adding prednisone to the other drug. She was struggling to breathe as the burns marched down her respiratory tract. Two days later, on March 5, with the severity of her burns reaching second degree, Grasham had to be moved to St. Mary's burn unit. SJS patients who reach this stage of damage - when more than 35 percent of the body is blistered or burned - are diagnosed with toxic epidermal necrolysis, or TENS. At that point, the mortality rate is around 50 percent. But after 18 days of intensive treatment - including extremely painful debriding of her burned skin, bandaging, infection control and special nursing care - Grasham finally left St. Mary's, alive but scarred. She has continued daily treatment as an outpatient.
"If only they had known what they were looking at in (El Paso) urgent care, I don't think this would have gotten so bad," her mother said. But many doctors will never see a case of Stevens-Johnson syndrome, said Dr. Jeffrey Nelson, a plastic surgeon and burn specialist at St. Mary's burn unit. Nelson - obviously familiar with it in his specialty - has treated about 10 to 12 cases during his nine years at St. Mary's, with antibiotics and anti-convulsants the most common trigger. "It feels like I've seen a lot more cases in the last three years than in the three years before that, but I have no way of knowing if that is an accurate trend," he said. SJS is not a reportable disease.
But warnings about the SJS-drug link have been emerging more frequently in recent years. In 1997, the Food and Drug Administration posted a warning on the drug Grasham took, Lamictal, and the drug's maker, Glaxo Wellcome, added a boxed, boldface warning to the drug's label saying the drug has caused "severe, potentially life-threatening rash, including Stevens-Johnson syndrome and, rarely, toxic epidermal necrolysis." The warning notes that the reaction is occurring in about one of every 1,000 adults taking the drug, but at dramatically higher rates in children - as high as one in 50.
"Lamictal is not approved for use in patients below the age of 16," the label now reads. Today, with no scholarship, her dreams of higher educations shot, she is at a loss over her future. "I just don't know. I need to find a job," she said softly. "This is such a nightmare."
For more Arizona news, visit www.azstarnet.com or www.azfamily.com.
© The Arizona Daily Star, 2004
Doctor-Mom Warns of Depakote Use for Treatment of Epilepsy
My nearly 9 year old with post-MMR regressive autism has chronic progressive complex partial epilepsy which has been treated with Depakote since 2/02. It was never discontinued despite lack of efficacy. Despite additional drugs and IVIG, the epilepsy was progressive. Finally he underwent epilepsy surgery last July and we breathed a sigh of relief: 85% improvement with clinical improvements as well.
Because we were not able to completely relieve the epilepsy, however, the anticonvulsants (Depakote and Keppra) were continued. Six months later, the epilepsy is back.... I just came across this correspondence and felt sick. Adam has measles virus F gene in his CSF--significant counts. We took a trip to the ER 41 days after the MMR for high fever and combativeness (very out of character) with no real 'explanation' clinically. He has autistic enterocolitis. So, although I have been assured by 'experts' that it must be a 'false positive' or 'just genetic material hanging around' (5 1/2 years after the one and only MMR?), it's real and I am sure alive and well--especially since it is very likely we have been 'feeding' it with a first-line, inexpensive anticonvulsant: Depakote. In vitro, Depakote increases replication of measles virus. It also increases CMV and HIV. I wouldn't be surprised if it increases replication of other viruses. We simply don't know.
I do not think our kids have SSPE, but I do think some of the kids with autism have measles living and replicating in their little bodies. There are many options for AEDs available. As an organic acid,
valproic acid may be more likely to increase viral replication than the newer anticonvulsants. Please post this correspondence and alert parents of children with epilepsy (especially complex partial epilepsy) and gut disease who think the MMR was the 'bullet' for their child. Even if their neurologist doesn't want to believe any of this, he or she may be uncomfortable prescribing an anticonvulsant that supports measles replication. Thanks. Correspondence below.
Debbie Darnley, M.D.
Pfizer pleads GUILTY, agrees to $430 million settlement in Neurontin case
http://www.katu.com/news/story.asp?ID=67300
Pfizer agrees to $430 million settlement in Neurontin case
By DENISE LAVOIE
BOSTON - Pfizer Inc. has agreed to plead guilty and pay $430 million in fines to settle charges that its Warner-Lambert unit flouted federal law by spending hundreds of thousands of dollars to promote non-approved uses of one of its drugs.
As part of the settlement announced Thursday, the world's largest pharmaceutical company will pay $24.6 million to whistleblower David Franklin, who first reported the marketing abuses. Under the agreement, the company acknowledged spending hundreds of thousands of dollars to promote non-approved uses for the anti- seizure drug Neurontin, in part by paying doctors hefty speakers' fees and flying them to lavish resorts as "educational" trips. Pfizer agreed to plead guilty to violating the Food, Drug and Cosmetic Act and pay a $240 million criminal fine, the second-largest ever in a criminal health care fraud prosecution, according to the Justice Department.
The company will also pay $152 million in civil fines to be shared among state and federal Medicaid agencies. Another $38 million would go to state consumer-protection agencies. Pfizer said the activity occurred years before it bought Warner- Lambert in 2000. "Pfizer is committed to compliance with all healthcare laws and FDA requirements and to high ethical standards in all aspects of its business practices," the company said in a statement. The case began in 1996, when Franklin filed a whistleblower lawsuit against Parke-Davis and its parent company Warner-Lambert, alleging it used an illegal marketing plan to drive up sales of the anti-seizure drug Neurontin in the 1990s.
The lawsuit alleged that while Neurontin was approved only as an epilepsy drug, the company promoted it for relieving pain, headaches, bipolar disorder and other psychiatric illnesses. While doctors can prescribe drugs for any use, the promotion of drugs for these so-called "off-label uses" is prohibited by the Food and Drug Cosmetic Act. "This illegal and fraudulent promotion scheme corrupted the information process relied upon by doctors in their medical decision-making, thereby putting patients at risk," said U.S. Attorney Michael Sullivan, who joined senior Justice Department officials in Washington to announce the settlement.
Franklin also alleged that he and other medical liaisons were instructed to lie about or exaggerate Neurontin's effectiveness for non-approved uses, including showing doctors one case study on a patient who used Neurontin and then telling doctors there were thousands of similar cases. "The primary victims here are the patients whose doctors might have made another decision if they had the right information," Franklinsaid in a recent interview with The Associated Press. Last May, federal prosecutors in Boston filed a brief in support of Franklin's lawsuit, and have since been in settlement negotiations with Pfizer to recover money the Medicaid program spent on Neurontin.
The whistleblower lawsuit alleged that the company's publicity plan for Neurontin included paying doctors to put their names on ghostwritten articles about Neurontin and to fly them to lavish resorts. One doctor received almost $308,000 to speak at conferences about the drug.
Neurontin's sales soared from $97.5 million in 1995 to nearly $2.7 billion in 2003.
The largest criminal fine in a health care fraud case was the $875 million paid in October 2001 by TAP Pharmaceutical Products Inc. for its marketing and pricing of the prostate cancer drug Lupron.
http://www.latimes.com/features/health/la-he-offlabel7jun07,1,2968921.story?coll=la-headlines-health
When drugs are used off-label
Doctors often prescribe medicines for other than their intended use. The benefits are well-proven, but the risks are often unknown.
By Daniel Costello, Special to The Times
After two months of sleepless nights, anxiety and constantly feeling like she was "swimming in a thick fog all day long," Caryl Westwood was fed up. She suspected her pain medication, Neurontin, which her doctor had recently prescribed for her lower back pain.
What Westwood didn't know — and she says her doctor didn't tell her — was that Neurontin wasn't a pain medication at all. Instead, it was a powerful epilepsy drug that doctors across the country were increasingly prescribing for many conditions for which the drug had not been approved: attention deficit disorder, migraines, drug and alcohol addiction, and pain. Surprisingly, there was little clear proof Neurontin worked for any of these conditions.
Although doctors are allowed to prescribe an FDA-approved drug for any reason they see fit, companies are barred from marketing or promoting drugs for any use beyond what's listed on its label. Last month, Pfizer Inc. agreed to plead guilty and pay a $430-million fine to settle federal criminal charges that the pharmaceutical giant promoted Neurontin for uses for which it had no scientific support.
According to the government's complaint, the promotion amounted to an "illegal and fraudulent promotion scheme" that put patients "at risk." It is estimated that 90% of Neurontin's $2.7 billion in sales last year were for off-label uses.
"I'm angry," says Westwood, a 52-year-old food service worker from Santa Fe, N.M. "How could a doctor not tell their patient about this? How can the government let this happen?"
Off-label prescription drugs are immensely common — accounting for up to 40% of all prescriptions written each year. In the vast majority of cases, the practice is safe. Moreover, off-label use has spawned many medical innovations that doctors might otherwise not have discovered.
It's how medical science first learned that aspirin could reduce the risk of heart disease; that antibiotics were the best way to treat ulcers; and that an angina drug produced an unexpected side effect in men, which would later lead to the development of the blockbuster drug Viagra.
Moreover, stories about the importance of off-label usage to treat life-threatening conditions such as AIDS and cancer are plentiful. Most front-line drugs used to treat terminal illnesses are approved for one purpose, but then quickly prescribed as a second or third option for patients with other illnesses who don't respond to traditional treatments. A 1997 survey by the American Cancer Society found that 60% of cancer doctors used drugs for unapproved reasons.
The American Medical Assn. says it strongly supports doctors' rights to prescribe FDA-approved drugs for any reasons that physicians believe are helpful. Such uses do not, as some critics charge, amount to turning patients into human guinea pigs, says Dr. Nancy Nielsen, a Buffalo, N.Y., internist and speaker of the AMA's House of Delegates. Doctors, she says, "are making decisions based on the best science and what's in the patient's best interest."
Still, the Neurontin case and other ongoing federal investigations into drug makers' promotions of off-label uses, indicate that the government is growing increasingly worried about the issue. The concern is that some drug companies are finding ways to abuse the system and promote their products for unapproved use even when they have little good science to back up their claims. Both Schering-Plough Corp. and Wyeth are being investigated by the federal government for their off-label prescription practices.
In some cases, taking a drug off- label may be a waste of money. As highly effective as some new drugs can be, older and cheaper drugs often are sometimes just as effective. In other cases, there's a risk to taking medications for conditions for which the FDA never evaluated the drug. It wasn't long ago, after all, that doctors were regularly prescribing fen-phen, a combination of two FDA-approved drugs — fenfluramine and phentermine — as an unapproved weight-loss treatment that was later suspected of causing heart valve damage in up to 30% of users.
Dr. Raymond Woosley, vice president of the Arizona Health Sciences Center at the University of Arizona in Tucson, says that most patients taking off-label drugs are getting the best treatment.
Even so, Woosley cautions that patients should be careful, especially when taking a relatively new drug that is being prescribed for several off-label uses, or when a drug is being used off-label for medical conditions not well understood by doctors and for which there are no "standard" treatments.
One example: drugs used to treat neurological conditions, such as depression, attention deficit disorder or anxiety. The brain "is still a vastly confusing area," he says, "and that's something drug companies can exploit."
Working the system
One important way that companies can circumvent regulations is by capitalizing on the different rules and accepted practices involving scientific research. In some cases, well-respected research articles demonstrating another use for an FDA-approved drug appear in major medical journals years before the agency catches up and endorses it.
In those cases, it's perfectly acceptable for drug companies to talk about those newly discovered benefits. The problem is, not all research is created equal. In some cases, drug companies conduct their own research and then hire ghostwriters to put their name on a paper before it's submitted for publication. (That relationship isn't always disclosed.)
As recently as the mid-'90s, the FDA tried to block companies from sending questionable research material directly to doctors. The agency was stymied by successful industry lawsuits claiming the practice was protected under free speech. The FDA still insists that drug companies can distribute research only after a physician has requested it.
There are ways around that too. Some doctors say that drug representatives start a conversation by saying they can't talk about off-label uses. But then, they will say that other doctors have used the drug for different reasons and they'd be happy to send along information about some ideas.
The AMA's Nielsen acknowledges that she and other physicians remain concerned about the increasing influence drug makers have over doctors' decision-making.
Mariann Caprino, a Pfizer spokeswoman, says the illegal activity highlighted in the Neurontin case happened before the company acquired Warner-Lambert in 2000.
Officials of Schering-Plough acknowledged in an interview that the company is under investigation by the U.S. Justice Department for off-label marketing of a cancer medication, while Wyeth said the federal Office of Personnel Management, the agency that oversees benefits for federal employees, has subpoenaed company records involving Wyeth's promotion of an antidepressant drug, Effexor.
Curbs in question
It's unclear just how effective the government's actions will be in curbing off-label marketing. Two years ago, the pharmaceutical industry instituted voluntary guidelines to ban most gifts and payments to doctors, which were aimed at slowing aggressive marketing tactics around both on-label and off-label promotions.
But some companies continue to underwrite seminars for doctors where off-label uses are discussed while others pay doctors to sit in the room with patients and discuss treatment advice, a financial agreement some characterize as quid pro quo payments.
Doctors are not required to tell patients they are writing off-label prescriptions, but many will discuss it if patients ask. Patients can also seek information about a drug's authorized uses on the FDA's website (www.fda.gov).
As part of its settlement agreement, Pfizer is required to spend a portion of its fine — $38 million — on a public-awareness campaign for doctors and patients.
After hearing about Pfizer's fine last month, Westwood says she decided to file a complaint against her doctor with the state medical board for not informing her Neurontin was not approved by the FDA as a pain medication and certain other uses. She realizes that the board is unlikely to act, but she remains resolute.
"I don't want anyone to have to go through this," she says. "It's not right."
PARENTS SUE MAKERS OF 'THE NEW THALIDOMIDE'
Oct 1 2004
By Lorraine Fisher
A GROUP of parents who claim their children were damaged by a drug dubbed "the new Thalidomide" are suing the makers.
Mothers allege that the anti-convulsant pill they took for epilepsy while they were pregnant left their babies with permanent mental and physical disabilities.
Children have been born with a variety of problems, including disfigured faces, spina bifida, autism, dyspraxia and dyslexia. Some have limb deformities like the victims of Thalidomide, which affected thousands of babies in the 1960s.
Three families have started legal action, suing manufacturers Sanofi-Synthelabo over its production of sodium valproate - a form of anti-convulsant. More drugs companies who make different types of anti-convulsants are expected to be included by the time the case reaches the courts in about two years.
The action is being brought under the 1987 Consumer Protection Act, which allows the child, rather than the mother, to bring a claim.
David Body, of the group's solicitors Irwin Mitchell, said: "To the baby the drug is not therapeutic. It is damaging." Mr Body said medical research had left him in no doubt that anti-convulsants had caused the problems.
Yesterday Sanofi-Synthelabo said: "All the proceedings relate to congenital abnormalities attributable to a wide range of possible causes; they are not specific to exposure to anti-epileptic drugs, including sodium valproate, during pregnancy."
http://www.medscape.com/viewarticle/492982_1
Valproic Acid-Induced Pancreatitis in Childhood Epilepsy: Case Series and Review
Posted 12/15/2004
D. Barry Sinclair, MD, FRCPC; Marjorie Berg, MSN; Rene Breault, BSc
Valproic acid (Depakene, Depakote, Epival) has been used in the treatment of childhood epilepsy for the past 25 years. Common side effects reported include nausea and vomiting, weight gain, hair loss, tremor, and, at higher doses, thrombocytopenia.[1] Liver abnormalities, including fatal hepatic necrosis, have been reported, particularly in young children under the age of 2 years, with multiple medication use.[2] Rarely, pancreatitis has been reported, usually as single case reports.[3-22] Recently, a case series of children with pancreatitis from valproic acid was reported,[23] suggesting that the problem might be more common than is appreciated. In the Pediatric Epilepsy Clinic of the Comprehensive Epilepsy Program at the University of Alberta, we recently encountered 11 patients on valproic acid who developed pancreatitis. A literature review and report of our series of patients follow.
The association between valproic acid and pancreatitis was first reported in an 8-year-old with absence seizures receiving valproic acid.[3] Soon after, in several letters to the editor, further reports of pancreatitis with valproic acid use were published.[4-6] Following these letters, there have been several case reports of pancreatitis in children receiving valproic acid for epilepsy.[7-23]
An early case report and review of the literature helped clearly establish valproic acid as a cause of pancreatitis and warned about the need to consider pancreatitis in any patient presenting with abdominal pain and vomiting.[7] This report, however, was published in the gastroenterology literature, and there appeared to be little recognition by child neurologists of the risk of pancreatitis for children taking valproic acid for epilepsy. In a small case series by Wyllie et al, four patients with valproic acid-induced pancreatitis were described, including their presentation and complications arising from the condition.
In one study, the largest to date, the authors reviewed their own clinic data, reviewed the literature, and arranged a survey of 507 epileptologists to try to determine the risk factors for valproic acid-induced pancreatitis.[22] Thirty-nine cases were reviewed. Pancreatitis in this study was found to be more frequent in the young (mean age 16.4 years) and had the highest risk during the first year of treatment, although it could occur any time. Seventy-six percent of the patients were on polytherapy, and 41% had a chronic encephalopathy. In most patients, early discontinuation of the drug resulted in successful resolution of the symptoms, as was our experience. Re-exposure of the patient to valproic acid was usually unsuccessful. Their conclusion, which is repeatedly encountered in the literature, is that awareness of the problem with early recognition of the pancreatitis and discontinuation of the drug is the most effective way to prevent long-term complications.
In the most recent series, four patients with valproic acid-induced pancreatitis were reported over a 4-year period, including a fatality, suggesting that in a child taking valproic acid with either abdominal pain or lethargy, pancreatitis should be considered. The authors recommended that serum lipase, amylase, and abdominal imaging be carried out.
We believe that valproic acid-induced pancreatitis is much more common than the literature would suggest and that awareness of this complication of valproic acid is essential in the health care professionals who treat children with epilepsy.
Conclusion
Pancreatitis is a severe adverse effect of valproic acid use in children with epilepsy and might be more common than is presently thought. Dose, duration of treatment, serum valproic acid levels, generic or brand-name preparation, and the presence of concomitant antiepileptic drugs do not appear to be risk factors. Children with known drug sensitivity might be at risk. Any child on valproic acid for epilepsy presenting with abdominal pain and vomiting or a flulike illness should be investigated for the possibility of valproic acid-induced pancreatitis.
J Intellect Disabil Res. 2005 Mar;49(Pt 3):183-9. Related Articles, Links
Topiramate in long-term treatment of epilepsy in the intellectually disabled.
Arvio M, Sillanpaa M.
Paajarvi Centre, Lammi, Turku University, Turku, Finland.
Abstract Background To study the effectiveness of topiramate (TPM) in refractory epilepsy in patients who have intellectual disability (ID). Methods A representative population sample of 57 patients with ID (age range 2-61, mean 32.8) was administered add-on TPM for drug-refractory epilepsy. Results Seizure freedom for at least for 6 months was attained by 10 (17%), and seizure reduction of >/= 50% by further 26 (46%). Less than 50% decrease in seizure frequency was found in 16 (29%). TPM was more efficacious in localisation-related than in generalised epilepsies (81% vs. 50%, P = 0.019). An at least 50% decrease in seizure frequency was achieved by patients with temporal lobe epilepsy in 100%, continuous spike-waves during sleep syndrome in 75%, Lennox-Gastaut syndrome in 52%, and those with infantile spasms in 25% of cases. As great decrease in seizure frequency was found in most patients with cortical dysplasia (83%), acquired encephalopathy with mesial temporal sclerosis (MTS) (75%), and genetic disease associated with MTS (66%). Adverse effects occurred in 10% including two (3%) with seizure aggravation and three (5%) necessitating discontinuation. Conclusion TPM is an effective antiepileptic drug which is of value in treating people with seizures that are resistant to other antiepileptic medication. As a broad-spectrum drug it may substitute for polypharmacy and, at the same time decrease adverse effects and costs of therapy.
PMID: 15713193 [PubMed - in process]
Studies in rat brains highlight risk of epileptic activity in immature neurons.
By Roxanne Khamsi.
http://www.nature.com/news/2005/051205/full/051205-5.html
Published online: 7 December 2005; | doi:10.1038/news051205-5
Experiments on immature rats' brains suggest that treating epileptic children with benzodiazepine drugs could do more harm than good, scientists in France have claimed. They have found that the neurotransmitters unlocked by these drugs cause changes in brain chemistry that actually promote epileptic activity. Anticonvulsant benzodiazepines are a last-ditch treatment used to stop seizures in both infants and adults. Some medical experts think that the electrical activity associated with seizures can change brain networks,
making them more susceptible to future epileptic activity. So understanding the chemistry of seizures might lead to drugs that can counteract epilepsy's development, says Yehezkel Ben-Ari, a neuroscientist at the Mediterranean Institute of Neurobiology in Marseille.
His team studied the electrical and chemical activity of brains removed from baby rats. They were particularly interested in the hippocampus, a part of the brain important in epileptic seizures. The researchers found that the neurotransmitter gamma-aminobutyric acid (GABA) triggers rapid electrical signalling in the immature hippocampus - a hallmark of epileptic seizures. Benzodiazepine drugs enhance the action of this neurotransmitter. Conversely, drugs that block nerve cells' GABA receptors seemed to prevent repeated seizures in the rats' brains. The team's results are published this week in Neuron1.
A lack of options
About a third of the 2.7 million epileptics in the United States are 17 or younger. Treatments include drugs and surgery. Recent studies have also suggested that a high-fat, low-carbohydrate diet reduces seizures in children with intractable epilepsy.
But therapy often fails. "Sixty to seventy percent of kids with epilepsy don't have effective treatment options," says Peter van Haverbeke, a spokesman for the Epilepsy Foundation in Landover, Maryland. Although benzodiazepine treatment is relatively rare, Ben-Ari says
that medics should still look more closely at the use of drugs that enhance GABA signalling. He speculates that too much GABA signalling in the very young can make chloride ions build up in immature neurons, predisposing them to further epilepsy.
Ben-Ari stresses that the adult brain is probably very different. There, GABA inhibits the fast electrical signalling associated with adult epilepsy. This may be connected with changes in the way chloride ions are transported in and out of neurons as the brain grows older, he explains.
Libor Velisek, a neuroscientist at the Albert Einstein College of Medicine in New York, suggests that doctors should also investigate whether pregnant women taking benzodiazepines could be predisposing their children to epilepsy: "I think that this may be an important issue," he says. Ben-Ari and his team are now studying the effects of benzodiazepines on neurons, hoping to find out if the drugs do indeed promote epileptic
signalling.
References Khalilov I., Le Van Quyen M., Gozlan H.& Ben-Ari Y. .
Neuron, 48. 787 - 796 Doi:10.1016/j.neuron.2005.09.026 (2005).
The negative repercussion of early-onset epilepsies on the immature brain is
unquestionable, with sometimes very intense impairment of cognitive
development.
Rev Neurol. 2007 May 21;44 Suppl 3:S43-5.
Links
[Cognitive repercussion of early-onset epilepsies.]
[Article in Spanish]
Herranz JL.
Hospital Universitario Marques de Valdecilla, 39008 Santander, Espana.
Introduction: From time to time the debate over whether early-onset epileptic seizures are harmless or have harmful effects on the developing brain reappears. <I>Development.<I/> We evaluated the results of clinical studies reporting the long-term cognitive development of children who suffer from early-onset epilepsies, that is to say, in children with brain immaturity: neonatal epilepsies, West's syndrome, Dravet's syndrome, benign myoclonic epilepsy in infancy, myoclonic-astatic epilepsy and Lennox-Gastaut syndrome; we also report on the harmful influence of certain antiepileptic drugs, such as phenobarbital and
valproate, on the immature brain.
Conclusions: The negative repercussion of early-onset epilepsies on the immature brain is unquestionable, with sometimes very intense impairment of cognitive development. As a result, we make the following recommendations: early electro-clinical diagnosis, immediate treatment, timely change of medication if the seizures persist, avoid phenobarbital and valproate, and try other drugs or compounds that have proved to have neuroprotective effects in experimental
studies.
PMID: 17523110 [PubMed - in process]
·an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives);
·liver damage (yellowing of the skin or eyes, nausea, abdominal pain or discomfort, severe fatigue);
·chest pain, high blood pressure (headache, flushing), or congestive heart failure (shortness of breath, swelling of ankles);
·numbness or tingling in the hands, feet, arms, or legs;
·body or muscle jerks;
·confusion, slurred speech, or fainting;
·continuing headache, hallucinations, or depression;
·severe nausea or vomiting;
·back-and-forth movements of the eyes;
·blurred or double vision; or
·decreased urination.
• Rarely, carbamazepine may cause serious blood problems. Notify your doctor immediately if you develop any of the following symptoms, which may be early signs of potential blood problems: fever, sore throat, rash, sores in the mouth, easy bruising, or red or purple bruising.
• Other, less serious side effects may be more likely to occur. Continue to take carbamazepine and talk to your doctor if you experience
·mild nausea, vomiting, diarrhea, constipation, or decreased appetite;
·dry mouth;
·joint or muscle aches or pains.
• Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.
If you experience any of the following serious side effects, contact your doctor immediately or seek emergency medical attention:
·an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives);
·liver damage (yellowing of the skin or eyes, nausea, abdominal pain or discomfort, severe fatigue);
·chest pain, high blood pressure (headache, flushing), or congestive heart failure (shortness of breath, swelling of ankles);
·numbness or tingling in the hands, feet, arms, or legs;
·body or muscle jerks;
·confusion, slurred speech, or fainting;
·continuing headache, hallucinations, or depression;
·severe nausea or vomiting;
·back-and-forth movements of the eyes;
·blurred or double vision; or
·decreased urination.
• Rarely, carbamazepine may cause serious blood problems. Notify your doctor immediately if you develop any of the following symptoms, which may be early signs of potential blood problems: fever, sore throat, rash, sores in the mouth, easy bruising, or red or purple bruising.
• Other, less serious side effects may be more likely to occur. Continue to take carbamazepine and talk to your doctor if you experience
·mild nausea, vomiting, diarrhea, constipation, or decreased appetite;
·dry mouth;
·joint or muscle aches or pains.
• Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.
"More children dying of drug side-effects"
(Western Morning News 28/11/02)
The number of suspected fatal side effects from drugs prescribed to children and reported by doctors has risen in the past decade, a new study revealed yesterday. The researchers found that anti-epileptic drugs were linked with the highest number of reported deaths and, in particular, liver damage. But the authors stressed that the overall benefit to children was likely to be far greater than the risk.
The study, published in the journal Archives of Disease in Childhood, looked at all suspected and fatal drug side effects in children and reported by doctors to the UK Medicines Control Agency (MCA) through its voluntary Yellow Card Scheme between 1964 and 2000. Vaccines and overdoses were excluded and no attempt was made to formally assess the cause of a child's death.
During this period 331 children aged up to 16 died and 390 suspect medicines were reported to the MCA. Altogether, almost half of the deaths occurred since 1991.
WHAT DOCTORS DON’T TELL YOU - E-NEWS BROADCAST No. 62 - 11 December 03
THE DRUGS DON'T WORK: And for once it's not us saying it, it's Glaxo
In an extraordinary admission, a senior executive with UK drug giant GlaxoSmithKline (GSK) has 'confessed' that the vast majority of prescription drugs don't work. Dr Allen Roses, worldwide vice-president of genetics at GSK, has told a conference that over 90 per cent of all drugs work for only between 30 per cent and 50 per cent of patients.
At the very bottom of the efficacy table are the cancer drugs, which work on only 25 per cent of patients. These are closely followed by Alzheimer's drugs that work on just 30 per cent of people. Drugs for rheumatoid arthritis, migraine, incontinence, hepatitis C, and diabetes work on only half the patients, at best. The most effective drugs are the analgesics, which work for to 80 per cent of those who take them.
This frank admission is also a very shocking one, and for several reasons. The pharmaceutical industry is about the most profitable in the world, and its profits are generated by drugs that everyone has implicitly believed would work (everyone apart from regular E-news readers, that is). Worse, in this scramble for profits, around 105,000 Americans and 40,000 Britons die every year from an adverse reaction to a drug, and many thousands more are permanently harmed from one.
Almost as astonishing has been the reaction from some of Roses's industry colleagues. "What he is saying will surprise the public but not his colleagues," said one industry scientist. Surprised may be a slight under-statement for the reaction of families who have lost a member to a drug-and one that the manufacturer probably knew would not work.
So it's no surprise to the drug companies. Is it a surprise, perhaps, to the drug regulators? Did they know that they were part of a scam? Or the government, maybe, that buys £7.2bn of drugs each year for the National Health Service? Are they also aware that at least two-thirds of that enormous expenditure is an utter waste?
How about the doctors? They are writing millions of prescriptions a year. Did they notice that their patients just weren't getting any better? Some commentators have described Roses's admission as a Ratner-like gaffe. For non-UK readers and those too young to remember, Gerald Ratner ran the UK's largest jewelers - until the day he 'joked' that his products were 'crap'.
But this was no Ratner moment. Roses knew full well what he was doing, and he almost certainly had his statement cleared by the very top executives at Glaxo. Roses has been described as a highly intelligent man, and he's certainly too smart to commit corporate suicide.
Roses is staking a major claim for his own division, into which Glaxo has poured billions of dollars of research money. Our guess is that Glaxo has taken the lead in the market, and will soon be launching a new approach to therapy, based on the patient's genetic make-up. In this new treatment model, patients will first be tested to discover the effectiveness of a drug, and if they are among the 20 per cent for whom the drug will work.
By allowing Roses to blow the whistle, Glaxo is playing a very high-risk game. Genetic profiling may be achievable, but it will cut drugs production by up to 80 per cent, so eating into profits. It may also not be a workable option, especially for an already overstretched health service. What then? We are just left with the information that most drugs don't work. Which is pretty much where we at WDDTY came in.
* Following on from Dr Roses's admission, you really must read the WDDTY book Secrets of the Drugs Industry. It lifts the lid on the drugs that don't work, those that are dangerous, and how the drugs industry masks its aggressive sales drives with supposed science. To order your copy, click on this link: http://www.wddty.co.uk/shop/details.asp?product=341
Her body burned by drug, not fire18-year-old has severe reaction to prescription
09:59 AM MST on Tuesday, May 4, 2004
By Carla McClain / Arizona Daily Star
A beautiful 18-year-old Tucson softball player has suffered severe burns over 80 percent of her body but has been nowhere near a fire. In an extremely rare, often fatal and little-known severe toxic reaction to a medical drug, Samantha Grasham's body caught fire - from the inside out - blistering most of her skin, as well as her mouth, throat, esophagus and airway, perhaps leaving her scarred for life. She spent nearly three weeks in the Burn Unit at St. Mary's Hospital, as doctors there worked to save her life and her skin.
As happens in most of these strange cases of what is known as Stevens-Johnson syndrome, there was no warning that Grasham would react so severely to a medication. Most people never know they are at risk, and doctors often do not recognize the syndrome when they see it. Yet many common drugs - including prescription painkillers and antibiotics - even over-the-counter pain and fever medicines for children - are linked to this "fire in the flesh."
In the worst cases, people are not only scarred, but also blinded and dependent on breathing and feeding tubes - if they survive. In its severe form, when the skin is literally burned off the body and even internal organs are damaged, about half die. The U.S. Food & Drug Administration has issued dozens of warnings about drugs that can trigger Stevens-Johnson syndrome (SJS) - including the one given to Grasham - but the warnings receive little publicity.
"I think it is commonly misdiagnosed, especially in the early stages," said Dr. Norman Levine, longtime University of Arizona dermatologist, who sees about one case a year. "But a physician will seldom miss it in a very sick patient, once it has severely progressed. When that happens, it can be devastating." Although the syndrome is rare - occurring at the rate of about 1 to 7 cases per million people per year - some say it is starting to increase significantly as more antibiotics and anti-inflammatory drugs hit the market. "The problem is that the drugs causing this syndrome are unbelievably common - things like ibuprofen, that people take every day," said Levine. "Something in the drug leads to a very inappropriate, wildly inflammatory immune response that causes the skin to die.
"It's completely unpredictable. Someone can be taking a drug safely for years, then all of a sudden have a horrible reaction to it. Those who get it are not highly allergic. This is just plain bad luck." In the case of Samantha Grasham, the syndrome stopped her life cold, ending her athletic scholarship, her education, her life plans. "I was always so active and involved - in sport and games. I loved college, and traveling," she said. "Now there is nothing - just these scars all over my body." Like many victims, she now battles chronic fatigue. The former softball star at Desert View High School entered El Paso Community College in Texas last fall on a two-year athletic scholarship. But in early January, during the first day of softball practice, she had an unexpected, one-time seizure that caused her to fall and black out.
After a series of tests back home in Tucson, Grasham was placed on an anti-seizure drug, Lamictal, by a neurologist, who told her she could return to school and go on with her life normally. She did, but about 10 days after starting the drug, she noticed a small rash on her arm. Though she played first base in a softball game the next day, the rash by then had spread to her arms, legs, back and face. With the rash worsening by the hour, now itching and burning, her ears and mouth starting to blister, Grasham went to urgent care in El Paso. A doctor there correctly diagnosed an allergic reaction to the drug she was taking but never told her to stop taking it - the first terrible mistake. After getting an allergy medicine, she was sent home.
Two days later, "my face was on fire," as Grasham describes it, and the burns were moving down her airway, interfering with her breathing. She went back to urgent care, where again no one told her to stop the drug. Instead they gave her another drug, prednisone, also linked to cases of Stevens-Johnson syndrome. The next day, her whole body now blistering and burning, her face completely inflamed, Grasham's family made an emergency trip to El Paso. "Oh my God, I couldn't even speak when I saw her. I couldn't even cry - I was so shocked," said her mother, Patricia Grasham. "Her mouth was one big blister; her face was all red and swollen. Her eyes were burning so bad we had to keep wet towels on them all the way home. The blisters were all over her mouth and down her throat. She was drooling, and in so much pain."
Driving straight to the emergency room at Tucson Medical Center, the family finally found out what had attacked their daughter. An emergency physician immediately diagnosed Stevens-Johnson syndrome and nailed Lamictal as the likely cause. Grasham remembers many doctors and nurses coming into her room to see this highly unusual and bizarre eruption, many of them for the first time. "Once you see the mucous membranes blistering, and you get a history of how this progressed in the patient, an emergency physician should know what they're looking at," said Dr. Ron Widman, chief of emergency services at TMC.
"But this is not very common, so yes, certainly, we want our young doctors to see it." Although Grasham was finally off Lamictal, the syndrome kept worsening - possibly fueled by adding prednisone to the other drug. She was struggling to breathe as the burns marched down her respiratory tract. Two days later, on March 5, with the severity of her burns reaching second degree, Grasham had to be moved to St. Mary's burn unit. SJS patients who reach this stage of damage - when more than 35 percent of the body is blistered or burned - are diagnosed with toxic epidermal necrolysis, or TENS. At that point, the mortality rate is around 50 percent. But after 18 days of intensive treatment - including extremely painful debriding of her burned skin, bandaging, infection control and special nursing care - Grasham finally left St. Mary's, alive but scarred. She has continued daily treatment as an outpatient.
"If only they had known what they were looking at in (El Paso) urgent care, I don't think this would have gotten so bad," her mother said. But many doctors will never see a case of Stevens-Johnson syndrome, said Dr. Jeffrey Nelson, a plastic surgeon and burn specialist at St. Mary's burn unit. Nelson - obviously familiar with it in his specialty - has treated about 10 to 12 cases during his nine years at St. Mary's, with antibiotics and anti-convulsants the most common trigger. "It feels like I've seen a lot more cases in the last three years than in the three years before that, but I have no way of knowing if that is an accurate trend," he said. SJS is not a reportable disease.
But warnings about the SJS-drug link have been emerging more frequently in recent years. In 1997, the Food and Drug Administration posted a warning on the drug Grasham took, Lamictal, and the drug's maker, Glaxo Wellcome, added a boxed, boldface warning to the drug's label saying the drug has caused "severe, potentially life-threatening rash, including Stevens-Johnson syndrome and, rarely, toxic epidermal necrolysis." The warning notes that the reaction is occurring in about one of every 1,000 adults taking the drug, but at dramatically higher rates in children - as high as one in 50.
"Lamictal is not approved for use in patients below the age of 16," the label now reads. Today, with no scholarship, her dreams of higher educations shot, she is at a loss over her future. "I just don't know. I need to find a job," she said softly. "This is such a nightmare."
For more Arizona news, visit www.azstarnet.com or www.azfamily.com.
© The Arizona Daily Star, 2004
Doctor-Mom Warns of Depakote Use for Treatment of Epilepsy
My nearly 9 year old with post-MMR regressive autism has chronic progressive complex partial epilepsy which has been treated with Depakote since 2/02. It was never discontinued despite lack of efficacy. Despite additional drugs and IVIG, the epilepsy was progressive. Finally he underwent epilepsy surgery last July and we breathed a sigh of relief: 85% improvement with clinical improvements as well.
Because we were not able to completely relieve the epilepsy, however, the anticonvulsants (Depakote and Keppra) were continued. Six months later, the epilepsy is back.... I just came across this correspondence and felt sick. Adam has measles virus F gene in his CSF--significant counts. We took a trip to the ER 41 days after the MMR for high fever and combativeness (very out of character) with no real 'explanation' clinically. He has autistic enterocolitis. So, although I have been assured by 'experts' that it must be a 'false positive' or 'just genetic material hanging around' (5 1/2 years after the one and only MMR?), it's real and I am sure alive and well--especially since it is very likely we have been 'feeding' it with a first-line, inexpensive anticonvulsant: Depakote. In vitro, Depakote increases replication of measles virus. It also increases CMV and HIV. I wouldn't be surprised if it increases replication of other viruses. We simply don't know.
I do not think our kids have SSPE, but I do think some of the kids with autism have measles living and replicating in their little bodies. There are many options for AEDs available. As an organic acid,
valproic acid may be more likely to increase viral replication than the newer anticonvulsants. Please post this correspondence and alert parents of children with epilepsy (especially complex partial epilepsy) and gut disease who think the MMR was the 'bullet' for their child. Even if their neurologist doesn't want to believe any of this, he or she may be uncomfortable prescribing an anticonvulsant that supports measles replication. Thanks. Correspondence below.
Debbie Darnley, M.D.
Pfizer pleads GUILTY, agrees to $430 million settlement in Neurontin case
http://www.katu.com/news/story.asp?ID=67300
Pfizer agrees to $430 million settlement in Neurontin case
By DENISE LAVOIE
BOSTON - Pfizer Inc. has agreed to plead guilty and pay $430 million in fines to settle charges that its Warner-Lambert unit flouted federal law by spending hundreds of thousands of dollars to promote non-approved uses of one of its drugs.
As part of the settlement announced Thursday, the world's largest pharmaceutical company will pay $24.6 million to whistleblower David Franklin, who first reported the marketing abuses. Under the agreement, the company acknowledged spending hundreds of thousands of dollars to promote non-approved uses for the anti- seizure drug Neurontin, in part by paying doctors hefty speakers' fees and flying them to lavish resorts as "educational" trips. Pfizer agreed to plead guilty to violating the Food, Drug and Cosmetic Act and pay a $240 million criminal fine, the second-largest ever in a criminal health care fraud prosecution, according to the Justice Department.
The company will also pay $152 million in civil fines to be shared among state and federal Medicaid agencies. Another $38 million would go to state consumer-protection agencies. Pfizer said the activity occurred years before it bought Warner- Lambert in 2000. "Pfizer is committed to compliance with all healthcare laws and FDA requirements and to high ethical standards in all aspects of its business practices," the company said in a statement. The case began in 1996, when Franklin filed a whistleblower lawsuit against Parke-Davis and its parent company Warner-Lambert, alleging it used an illegal marketing plan to drive up sales of the anti-seizure drug Neurontin in the 1990s.
The lawsuit alleged that while Neurontin was approved only as an epilepsy drug, the company promoted it for relieving pain, headaches, bipolar disorder and other psychiatric illnesses. While doctors can prescribe drugs for any use, the promotion of drugs for these so-called "off-label uses" is prohibited by the Food and Drug Cosmetic Act. "This illegal and fraudulent promotion scheme corrupted the information process relied upon by doctors in their medical decision-making, thereby putting patients at risk," said U.S. Attorney Michael Sullivan, who joined senior Justice Department officials in Washington to announce the settlement.
Franklin also alleged that he and other medical liaisons were instructed to lie about or exaggerate Neurontin's effectiveness for non-approved uses, including showing doctors one case study on a patient who used Neurontin and then telling doctors there were thousands of similar cases. "The primary victims here are the patients whose doctors might have made another decision if they had the right information," Franklinsaid in a recent interview with The Associated Press. Last May, federal prosecutors in Boston filed a brief in support of Franklin's lawsuit, and have since been in settlement negotiations with Pfizer to recover money the Medicaid program spent on Neurontin.
The whistleblower lawsuit alleged that the company's publicity plan for Neurontin included paying doctors to put their names on ghostwritten articles about Neurontin and to fly them to lavish resorts. One doctor received almost $308,000 to speak at conferences about the drug.
Neurontin's sales soared from $97.5 million in 1995 to nearly $2.7 billion in 2003.
The largest criminal fine in a health care fraud case was the $875 million paid in October 2001 by TAP Pharmaceutical Products Inc. for its marketing and pricing of the prostate cancer drug Lupron.
http://www.latimes.com/features/health/la-he-offlabel7jun07,1,2968921.story?coll=la-headlines-health
When drugs are used off-label
Doctors often prescribe medicines for other than their intended use. The benefits are well-proven, but the risks are often unknown.
By Daniel Costello, Special to The Times
After two months of sleepless nights, anxiety and constantly feeling like she was "swimming in a thick fog all day long," Caryl Westwood was fed up. She suspected her pain medication, Neurontin, which her doctor had recently prescribed for her lower back pain.
What Westwood didn't know — and she says her doctor didn't tell her — was that Neurontin wasn't a pain medication at all. Instead, it was a powerful epilepsy drug that doctors across the country were increasingly prescribing for many conditions for which the drug had not been approved: attention deficit disorder, migraines, drug and alcohol addiction, and pain. Surprisingly, there was little clear proof Neurontin worked for any of these conditions.
Although doctors are allowed to prescribe an FDA-approved drug for any reason they see fit, companies are barred from marketing or promoting drugs for any use beyond what's listed on its label. Last month, Pfizer Inc. agreed to plead guilty and pay a $430-million fine to settle federal criminal charges that the pharmaceutical giant promoted Neurontin for uses for which it had no scientific support.
According to the government's complaint, the promotion amounted to an "illegal and fraudulent promotion scheme" that put patients "at risk." It is estimated that 90% of Neurontin's $2.7 billion in sales last year were for off-label uses.
"I'm angry," says Westwood, a 52-year-old food service worker from Santa Fe, N.M. "How could a doctor not tell their patient about this? How can the government let this happen?"
Off-label prescription drugs are immensely common — accounting for up to 40% of all prescriptions written each year. In the vast majority of cases, the practice is safe. Moreover, off-label use has spawned many medical innovations that doctors might otherwise not have discovered.
It's how medical science first learned that aspirin could reduce the risk of heart disease; that antibiotics were the best way to treat ulcers; and that an angina drug produced an unexpected side effect in men, which would later lead to the development of the blockbuster drug Viagra.
Moreover, stories about the importance of off-label usage to treat life-threatening conditions such as AIDS and cancer are plentiful. Most front-line drugs used to treat terminal illnesses are approved for one purpose, but then quickly prescribed as a second or third option for patients with other illnesses who don't respond to traditional treatments. A 1997 survey by the American Cancer Society found that 60% of cancer doctors used drugs for unapproved reasons.
The American Medical Assn. says it strongly supports doctors' rights to prescribe FDA-approved drugs for any reasons that physicians believe are helpful. Such uses do not, as some critics charge, amount to turning patients into human guinea pigs, says Dr. Nancy Nielsen, a Buffalo, N.Y., internist and speaker of the AMA's House of Delegates. Doctors, she says, "are making decisions based on the best science and what's in the patient's best interest."
Still, the Neurontin case and other ongoing federal investigations into drug makers' promotions of off-label uses, indicate that the government is growing increasingly worried about the issue. The concern is that some drug companies are finding ways to abuse the system and promote their products for unapproved use even when they have little good science to back up their claims. Both Schering-Plough Corp. and Wyeth are being investigated by the federal government for their off-label prescription practices.
In some cases, taking a drug off- label may be a waste of money. As highly effective as some new drugs can be, older and cheaper drugs often are sometimes just as effective. In other cases, there's a risk to taking medications for conditions for which the FDA never evaluated the drug. It wasn't long ago, after all, that doctors were regularly prescribing fen-phen, a combination of two FDA-approved drugs — fenfluramine and phentermine — as an unapproved weight-loss treatment that was later suspected of causing heart valve damage in up to 30% of users.
Dr. Raymond Woosley, vice president of the Arizona Health Sciences Center at the University of Arizona in Tucson, says that most patients taking off-label drugs are getting the best treatment.
Even so, Woosley cautions that patients should be careful, especially when taking a relatively new drug that is being prescribed for several off-label uses, or when a drug is being used off-label for medical conditions not well understood by doctors and for which there are no "standard" treatments.
One example: drugs used to treat neurological conditions, such as depression, attention deficit disorder or anxiety. The brain "is still a vastly confusing area," he says, "and that's something drug companies can exploit."
Working the system
One important way that companies can circumvent regulations is by capitalizing on the different rules and accepted practices involving scientific research. In some cases, well-respected research articles demonstrating another use for an FDA-approved drug appear in major medical journals years before the agency catches up and endorses it.
In those cases, it's perfectly acceptable for drug companies to talk about those newly discovered benefits. The problem is, not all research is created equal. In some cases, drug companies conduct their own research and then hire ghostwriters to put their name on a paper before it's submitted for publication. (That relationship isn't always disclosed.)
As recently as the mid-'90s, the FDA tried to block companies from sending questionable research material directly to doctors. The agency was stymied by successful industry lawsuits claiming the practice was protected under free speech. The FDA still insists that drug companies can distribute research only after a physician has requested it.
There are ways around that too. Some doctors say that drug representatives start a conversation by saying they can't talk about off-label uses. But then, they will say that other doctors have used the drug for different reasons and they'd be happy to send along information about some ideas.
The AMA's Nielsen acknowledges that she and other physicians remain concerned about the increasing influence drug makers have over doctors' decision-making.
Mariann Caprino, a Pfizer spokeswoman, says the illegal activity highlighted in the Neurontin case happened before the company acquired Warner-Lambert in 2000.
Officials of Schering-Plough acknowledged in an interview that the company is under investigation by the U.S. Justice Department for off-label marketing of a cancer medication, while Wyeth said the federal Office of Personnel Management, the agency that oversees benefits for federal employees, has subpoenaed company records involving Wyeth's promotion of an antidepressant drug, Effexor.
Curbs in question
It's unclear just how effective the government's actions will be in curbing off-label marketing. Two years ago, the pharmaceutical industry instituted voluntary guidelines to ban most gifts and payments to doctors, which were aimed at slowing aggressive marketing tactics around both on-label and off-label promotions.
But some companies continue to underwrite seminars for doctors where off-label uses are discussed while others pay doctors to sit in the room with patients and discuss treatment advice, a financial agreement some characterize as quid pro quo payments.
Doctors are not required to tell patients they are writing off-label prescriptions, but many will discuss it if patients ask. Patients can also seek information about a drug's authorized uses on the FDA's website (www.fda.gov).
As part of its settlement agreement, Pfizer is required to spend a portion of its fine — $38 million — on a public-awareness campaign for doctors and patients.
After hearing about Pfizer's fine last month, Westwood says she decided to file a complaint against her doctor with the state medical board for not informing her Neurontin was not approved by the FDA as a pain medication and certain other uses. She realizes that the board is unlikely to act, but she remains resolute.
"I don't want anyone to have to go through this," she says. "It's not right."
PARENTS SUE MAKERS OF 'THE NEW THALIDOMIDE'
Oct 1 2004
By Lorraine Fisher
A GROUP of parents who claim their children were damaged by a drug dubbed "the new Thalidomide" are suing the makers.
Mothers allege that the anti-convulsant pill they took for epilepsy while they were pregnant left their babies with permanent mental and physical disabilities.
Children have been born with a variety of problems, including disfigured faces, spina bifida, autism, dyspraxia and dyslexia. Some have limb deformities like the victims of Thalidomide, which affected thousands of babies in the 1960s.
Three families have started legal action, suing manufacturers Sanofi-Synthelabo over its production of sodium valproate - a form of anti-convulsant. More drugs companies who make different types of anti-convulsants are expected to be included by the time the case reaches the courts in about two years.
The action is being brought under the 1987 Consumer Protection Act, which allows the child, rather than the mother, to bring a claim.
David Body, of the group's solicitors Irwin Mitchell, said: "To the baby the drug is not therapeutic. It is damaging." Mr Body said medical research had left him in no doubt that anti-convulsants had caused the problems.
Yesterday Sanofi-Synthelabo said: "All the proceedings relate to congenital abnormalities attributable to a wide range of possible causes; they are not specific to exposure to anti-epileptic drugs, including sodium valproate, during pregnancy."
http://www.medscape.com/viewarticle/492982_1
Valproic Acid-Induced Pancreatitis in Childhood Epilepsy: Case Series and Review
Posted 12/15/2004
D. Barry Sinclair, MD, FRCPC; Marjorie Berg, MSN; Rene Breault, BSc
Valproic acid (Depakene, Depakote, Epival) has been used in the treatment of childhood epilepsy for the past 25 years. Common side effects reported include nausea and vomiting, weight gain, hair loss, tremor, and, at higher doses, thrombocytopenia.[1] Liver abnormalities, including fatal hepatic necrosis, have been reported, particularly in young children under the age of 2 years, with multiple medication use.[2] Rarely, pancreatitis has been reported, usually as single case reports.[3-22] Recently, a case series of children with pancreatitis from valproic acid was reported,[23] suggesting that the problem might be more common than is appreciated. In the Pediatric Epilepsy Clinic of the Comprehensive Epilepsy Program at the University of Alberta, we recently encountered 11 patients on valproic acid who developed pancreatitis. A literature review and report of our series of patients follow.
The association between valproic acid and pancreatitis was first reported in an 8-year-old with absence seizures receiving valproic acid.[3] Soon after, in several letters to the editor, further reports of pancreatitis with valproic acid use were published.[4-6] Following these letters, there have been several case reports of pancreatitis in children receiving valproic acid for epilepsy.[7-23]
An early case report and review of the literature helped clearly establish valproic acid as a cause of pancreatitis and warned about the need to consider pancreatitis in any patient presenting with abdominal pain and vomiting.[7] This report, however, was published in the gastroenterology literature, and there appeared to be little recognition by child neurologists of the risk of pancreatitis for children taking valproic acid for epilepsy. In a small case series by Wyllie et al, four patients with valproic acid-induced pancreatitis were described, including their presentation and complications arising from the condition.
In one study, the largest to date, the authors reviewed their own clinic data, reviewed the literature, and arranged a survey of 507 epileptologists to try to determine the risk factors for valproic acid-induced pancreatitis.[22] Thirty-nine cases were reviewed. Pancreatitis in this study was found to be more frequent in the young (mean age 16.4 years) and had the highest risk during the first year of treatment, although it could occur any time. Seventy-six percent of the patients were on polytherapy, and 41% had a chronic encephalopathy. In most patients, early discontinuation of the drug resulted in successful resolution of the symptoms, as was our experience. Re-exposure of the patient to valproic acid was usually unsuccessful. Their conclusion, which is repeatedly encountered in the literature, is that awareness of the problem with early recognition of the pancreatitis and discontinuation of the drug is the most effective way to prevent long-term complications.
In the most recent series, four patients with valproic acid-induced pancreatitis were reported over a 4-year period, including a fatality, suggesting that in a child taking valproic acid with either abdominal pain or lethargy, pancreatitis should be considered. The authors recommended that serum lipase, amylase, and abdominal imaging be carried out.
We believe that valproic acid-induced pancreatitis is much more common than the literature would suggest and that awareness of this complication of valproic acid is essential in the health care professionals who treat children with epilepsy.
Conclusion
Pancreatitis is a severe adverse effect of valproic acid use in children with epilepsy and might be more common than is presently thought. Dose, duration of treatment, serum valproic acid levels, generic or brand-name preparation, and the presence of concomitant antiepileptic drugs do not appear to be risk factors. Children with known drug sensitivity might be at risk. Any child on valproic acid for epilepsy presenting with abdominal pain and vomiting or a flulike illness should be investigated for the possibility of valproic acid-induced pancreatitis.
J Intellect Disabil Res. 2005 Mar;49(Pt 3):183-9. Related Articles, Links
Topiramate in long-term treatment of epilepsy in the intellectually disabled.
Arvio M, Sillanpaa M.
Paajarvi Centre, Lammi, Turku University, Turku, Finland.
Abstract Background To study the effectiveness of topiramate (TPM) in refractory epilepsy in patients who have intellectual disability (ID). Methods A representative population sample of 57 patients with ID (age range 2-61, mean 32.8) was administered add-on TPM for drug-refractory epilepsy. Results Seizure freedom for at least for 6 months was attained by 10 (17%), and seizure reduction of >/= 50% by further 26 (46%). Less than 50% decrease in seizure frequency was found in 16 (29%). TPM was more efficacious in localisation-related than in generalised epilepsies (81% vs. 50%, P = 0.019). An at least 50% decrease in seizure frequency was achieved by patients with temporal lobe epilepsy in 100%, continuous spike-waves during sleep syndrome in 75%, Lennox-Gastaut syndrome in 52%, and those with infantile spasms in 25% of cases. As great decrease in seizure frequency was found in most patients with cortical dysplasia (83%), acquired encephalopathy with mesial temporal sclerosis (MTS) (75%), and genetic disease associated with MTS (66%). Adverse effects occurred in 10% including two (3%) with seizure aggravation and three (5%) necessitating discontinuation. Conclusion TPM is an effective antiepileptic drug which is of value in treating people with seizures that are resistant to other antiepileptic medication. As a broad-spectrum drug it may substitute for polypharmacy and, at the same time decrease adverse effects and costs of therapy.
PMID: 15713193 [PubMed - in process]
Studies in rat brains highlight risk of epileptic activity in immature neurons.
By Roxanne Khamsi.
http://www.nature.com/news/2005/051205/full/051205-5.html
Published online: 7 December 2005; | doi:10.1038/news051205-5
Experiments on immature rats' brains suggest that treating epileptic children with benzodiazepine drugs could do more harm than good, scientists in France have claimed. They have found that the neurotransmitters unlocked by these drugs cause changes in brain chemistry that actually promote epileptic activity. Anticonvulsant benzodiazepines are a last-ditch treatment used to stop seizures in both infants and adults. Some medical experts think that the electrical activity associated with seizures can change brain networks,
making them more susceptible to future epileptic activity. So understanding the chemistry of seizures might lead to drugs that can counteract epilepsy's development, says Yehezkel Ben-Ari, a neuroscientist at the Mediterranean Institute of Neurobiology in Marseille.
His team studied the electrical and chemical activity of brains removed from baby rats. They were particularly interested in the hippocampus, a part of the brain important in epileptic seizures. The researchers found that the neurotransmitter gamma-aminobutyric acid (GABA) triggers rapid electrical signalling in the immature hippocampus - a hallmark of epileptic seizures. Benzodiazepine drugs enhance the action of this neurotransmitter. Conversely, drugs that block nerve cells' GABA receptors seemed to prevent repeated seizures in the rats' brains. The team's results are published this week in Neuron1.
A lack of options
About a third of the 2.7 million epileptics in the United States are 17 or younger. Treatments include drugs and surgery. Recent studies have also suggested that a high-fat, low-carbohydrate diet reduces seizures in children with intractable epilepsy.
But therapy often fails. "Sixty to seventy percent of kids with epilepsy don't have effective treatment options," says Peter van Haverbeke, a spokesman for the Epilepsy Foundation in Landover, Maryland. Although benzodiazepine treatment is relatively rare, Ben-Ari says
that medics should still look more closely at the use of drugs that enhance GABA signalling. He speculates that too much GABA signalling in the very young can make chloride ions build up in immature neurons, predisposing them to further epilepsy.
Ben-Ari stresses that the adult brain is probably very different. There, GABA inhibits the fast electrical signalling associated with adult epilepsy. This may be connected with changes in the way chloride ions are transported in and out of neurons as the brain grows older, he explains.
Libor Velisek, a neuroscientist at the Albert Einstein College of Medicine in New York, suggests that doctors should also investigate whether pregnant women taking benzodiazepines could be predisposing their children to epilepsy: "I think that this may be an important issue," he says. Ben-Ari and his team are now studying the effects of benzodiazepines on neurons, hoping to find out if the drugs do indeed promote epileptic
signalling.
References Khalilov I., Le Van Quyen M., Gozlan H.& Ben-Ari Y. .
Neuron, 48. 787 - 796 Doi:10.1016/j.neuron.2005.09.026 (2005).
The negative repercussion of early-onset epilepsies on the immature brain is
unquestionable, with sometimes very intense impairment of cognitive
development.
Rev Neurol. 2007 May 21;44 Suppl 3:S43-5.
Links
[Cognitive repercussion of early-onset epilepsies.]
[Article in Spanish]
Herranz JL.
Hospital Universitario Marques de Valdecilla, 39008 Santander, Espana.
Introduction: From time to time the debate over whether early-onset epileptic seizures are harmless or have harmful effects on the developing brain reappears. <I>Development.<I/> We evaluated the results of clinical studies reporting the long-term cognitive development of children who suffer from early-onset epilepsies, that is to say, in children with brain immaturity: neonatal epilepsies, West's syndrome, Dravet's syndrome, benign myoclonic epilepsy in infancy, myoclonic-astatic epilepsy and Lennox-Gastaut syndrome; we also report on the harmful influence of certain antiepileptic drugs, such as phenobarbital and
valproate, on the immature brain.
Conclusions: The negative repercussion of early-onset epilepsies on the immature brain is unquestionable, with sometimes very intense impairment of cognitive development. As a result, we make the following recommendations: early electro-clinical diagnosis, immediate treatment, timely change of medication if the seizures persist, avoid phenobarbital and valproate, and try other drugs or compounds that have proved to have neuroprotective effects in experimental
studies.
PMID: 17523110 [PubMed - in process]
