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Anti Seizure Medication
Potiga (ezogabine): Drug Safety Communication - FDA Determines 2013 Labeling Adequate to Manage Risks of Retinal Abnormalities, Potential Vision Loss, and Skin Discoloration
AUDIENCE: Neurology, Eye Care, Dermatology
ISSUE: Based on reviews of additional safety reports from patients treated with the anti-seizure drug Potiga (ezogabine), the FDA has determined that the potential risks of vision loss due to pigment changes in the retina and of skin discoloration can be adequately managed by following the current recommendations in the Potiga labeling. To further explore any potential long-term consequences of these pigment changes, FDA has required the Potiga manufacturer, GlaxoSmithKline, to conduct a long-term observational study.
FDA review of additional safety reports does not indicate that the pigment changes in the retina observed in some patients affect vision. Skin discoloration associated with the use of Potiga appears to be a cosmetic effect and does not appear to be associated with more serious adverse effects. Therefore, a modification of the Risk Evaluation and Mitigation Strategy (REMS) is not needed at this time to ensure that the benefits of Potiga outweigh the risks of retinal and skin pigment changes. FDA expects that the required long-term observational study will provide further information on whether pigment changes in the retina caused by Potiga can lead to vision loss or other long-term side effects. In addition, the study should provide more information on the relationship between pigment changes in the retina and skin discoloration.
BACKGROUND: Potiga is approved for use in combination with other anti-seizure drugs to treat partial-onset seizures in adult patients who have had an inadequate response to several alternative therapies and for whom the benefits of treatment outweigh the risks.
RECOMMENDATION: Health care professionals should continue to follow the recommendations provided in the Boxed Warning, FDA’s most serious type of warning, and the Warnings and Precautions and Indications and Usage sections of the labeling.
Source : FDA (June 2015)
FDA Drug Safety Communication: FDA warns of serious skin reactions with the anti-seizure drug Onfi (clobazam) and has approved label changes
The U.S. Food and Drug Administration (FDA) is warning the public that the anti-seizure drug Onfi (clobazam) can cause rare but serious skin reactions that can result in permanent harm and death. We have approved changes to the Onfi drug label and the patient Medication Guide to describe the risk of these serious skin reactions. Patients taking Onfi should seek immediate medical treatment if they develop a rash, blistering or peeling of the skin, sores in the mouth, or hives. Health care professionals should discontinue use of Onfi and consider an alternate therapy at the first sign of rash, unless it is clearly not drug-related. These rare but serious skin reactions, called Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), can occur at any time during Onfi treatment. However, the likelihood of skin reactions is greater during the first 8 weeks of treatment or when Onfi is stopped and then re-started. All cases of SJS and TEN in the FDA case series have resulted in hospitalization, one case resulted in blindness, and one case resulted in death.
Onfi is a benzodiazepine medication used in combination with other medicines to treat seizures associated with a severe form of epilepsy called Lennox-Gastaut Syndrome. Serious skin reactions have not generally been associated with other benzodiazepines.
Patients should not stop taking Onfi without first talking to their health care professionals. Stopping Onfi suddenly can cause serious withdrawal problems, such as seizures that will not stop, hallucinations (hearing or seeing things that are not real), shaking, nervousness, and stomach or muscle cramps.
Source : FDA (Dec. 2013)
FDA Drug Safety Communication: Valproate Anti-seizure Products Contraindicated for Migraine Prevention in Pregnant Women due to Decreased IQ Scores in Exposed Children
The U.S. Food and Drug Administration (FDA) is advising health care professionals and women that the anti-seizure medication valproate sodium and related products, valproic acid and divalproex sodium, are contraindicated and should not be taken by pregnant women for the prevention of migraine headaches. Based on information from a recent study, there is evidence that these medications can cause decreased IQ scores in children whose mothers took them while pregnant.1 Stronger warnings about use during pregnancy will be added to the drug labels, and valproate’s pregnancy category for migraine use will be changed from "D" (the potential benefit of the drug in pregnant women may be acceptable despite its potential risks) to "X" (the risk of use in pregnant women clearly outweighs any possible benefit of the drug).With regard to valproate use in pregnant women with epilepsy or bipolar disorder, valproate products should only be prescribed if other medications are not effective in treating the condition or are otherwise unacceptable. Valproate products will remain in pregnancy category D for treating epilepsy and manic episodes associated with bipolar disorder.
With regard to women of childbearing age who are not pregnant, valproate should not be taken for any condition unless the drug is essential to the management of the woman's medical condition. All non-pregnant women of childbearing age taking valproate products should use effective birth control.
Valproate products include: valproate sodium (Depacon), divalproex sodium (Depakote, Depakote CP, and Depakote ER), valproic acid (Depakene and Stavzor), and their generics.
This alert is based on the final results of the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study showing that children exposed to valproate products while their mothers were pregnant had decreased IQs at age 6 compared to children exposed to other anti-epileptic drugs (see Data Summary).1 The difference in average IQ between the children who had been exposed to valproate and the children who had been exposed to other antiepileptic drugs varied between 8 and 11 points depending on the drug to which valproate was compared.
FDA previously communicated initial findings about this risk in a June 2011 Drug Safety Communication. At that time, FDA also worked with valproate manufacturers to revise the drug labels after interim results from the NEAD study showed lower cognitive test scores at age 3 in children exposed to valproate compared to children exposed to other antiepileptic drugs.2
Women who are pregnant and taking a valproate medication should not stop their medication but should talk to their health care professionals immediately. Stopping valproate treatment suddenly can cause serious and life-threatening medical problems to the woman or her baby.
It is not known whether there is a specific time period during pregnancy when valproate exposure can result in negative cognitive effects. Similarly, there is no known time during pregnancy in which exposure may be considered to have less risk for decreased IQ in children. Because the women in the NEAD study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed.
FDA is working with manufacturers to change the drug labels for valproate products with this updated risk information. FDA continues to evaluate information about the potential risks of valproate use during pregnancy and will update the public as more information becomes available.
Pregnancy Category X means that studies in animals or humans have shown positive evidence of fetal risk, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefits. Category D means there is positive evidence of risk to a baby based on data from studies or other experience in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.
Source : FDA (May 2013)
Potiga (Ezogabine): Drug Safety Communication - Linked To Retinal Abnormalities And Blue Skin Discoloration
ISSUE: FDA is warning the public that the anti-seizure medication Potiga (Ezogabine) can cause blue skin discoloration and eye abnormalities characterized by pigment changes in the retina. FDA does not currently know if these changes are reversible. FDA is working with the manufacturer to gather and evaluate all available information to better understand these events. FDA will update the public when more information is available.
BACKGROUND: Potiga is approved as adjunctive (added on to other anti-seizure medications) treatment of partial-onset seizures in adult patients 18 years and older. The skin discoloration in the reported cases appeared as blue pigmentation, predominantly on or around the lips or in the nail beds of the fingers or toes, but more widespread involvement of the face and legs has also been reported. Scleral and conjunctival discoloration, on the white of the eye and inside eyelids, has been observed as well. The skin discoloration generally occurred after four years of treatment with Potiga, but has appeared sooner in some patients. In some cases, retinal abnormalities have been observed in the absence of skin discoloration.
RECOMMENDATION: All patients taking Potiga should have a baseline eye exam and periodic eye exams that should include visual acuity testing and dilated fundus photography, and may include fluorescein angiograms (FA), ocular coherence tomography (OCT), perimetry, and electroretinograms (ERG). Patients who are taking Potiga and develop any changes in your vision or any discoloration of your skin, including of your lips and nail beds should contact their health care professional right away. Patients should not stop taking Potiga without talking to their health care professional. Stopping such treatment suddenly can cause serious and life-threatening medical problems such as recurrence of seizures.
Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety
Source - FDA Safety Communication - FDA]
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Epilepsy drug in pregnancy tied to autism risk
Women who take the epilepsy drug valproate during pregnancy are three times more likely to have a child with an autism spectrum disorder, suggests new research based on close to 700,000 babies born in Denmark.
Previous studies have found more birth defects and lower intelligence among children of mothers who took valproate, but the new work represents the "strongest evidence to date" of a link between the drug and autism, according to an editorial published with the study on Tuesday.
The results don't prove the generic drug, also sold as valproic acid, causes autism. But researchers were able to account for a number of underlying factors - such as the age and health of the mothers and the babies' fathers - that make the study more convincing, Christopher Stodgell said.
"This finding isn't necessarily a brand new finding, but it's an important finding in that (researchers studied) really a much larger population, and they also looked at some other underlying drivers," said Stodgell, who studies the origins of autism at the University of Rochester Medical Center but wasn't involved in the new research.
Women "need to be very diligent about what the effects are if they're taking valproic acid," he told Reuters Health.
About one in 88 children has an autism spectrum disorder, or ASD, according to the U.S. Centers for Disease Control and Prevention. Those conditions range from autism itself to less disabling ones such as Asperger's syndrome.
For the new study, researchers tracked 656,000 kids born in Denmark between 1996 and 2006. Using a large prescription drug database, they found that just under 6,600 of the mothers of those children had epilepsy and 508 women took valproate while pregnant.
By 2010, 4.4 percent of the kids whose mothers had taken valproate during pregnancy were diagnosed with any ASD, including 2.5 percent with autism.
In contrast, 1.5 percent of all babies in the study had an ASD and 0.5 percent had autism, the study team reported in the Journal of the American Medical Association.
Mothers' underlying epilepsy didn't fully explain the link, according to Jakob Christensen from Aarhus University and his colleagues. In addition, autism rates were higher among children of women who used valproate during pregnancy than those who had previously used the drug but stopped before conceiving.
CONSIDER RISKS, BENEFITS
"Valproate is an effective drug, but it appears that it is being prescribed for women of childbearing potential at a rate that does not fully consider the ratio of benefits to risks," wrote Dr. Kimford Meador and David Loring from Emory University in Atlanta, in a linked editorial.
Valproate could affect maturation of a fetus's brain, Christensen suggested, including the signal-sending neurotransmitters.
Women who may become pregnant "certainly should discuss with their doctor if there are alternative treatments that would be reasonable," he told Reuters Health.
For those with certain syndromes or generalized epilepsy, there aren't necessarily other good options. Stopping valproate in that case isn't a good idea, Christensen said.
"It's also a risk if you have seizures, both for the mother and the unborn child. (Stopping medication) is not a thing that you take lightly," he said.
"Even those that are exposed to this drug, there's still a good chance - more than a 95-percent chance - that their child will never develop signs of autism."
The study didn't take into account whether women drank during pregnancy, or if they took folic acid - which has been tied to a lower risk of some birth defects.
Christensen said there are steps pregnant women on valproate can take to lower any risks to their baby, such as using the lowest possible dose and dividing it up during the day.
Source : Reuters via bit.ly/JjFzqx Journal of the American Medical Association, online April 23, 2013.
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Why are doctors still not warning about the 'new Thalidomide'? Mother tells how taking an anti-epileptic drug while pregnant devastated the heath of two of her children
In 2008, Emma Murphy phoned her partner Joe at work. ‘I know what’s wrong with the children,’ she said.
For four years the couple had been perplexed by the health problems that affected their daughters Chloe and Lauren and their son Luke – and their GP had consistently dismissed their concerns.
It was only after watching a television programme about Fetal Anticonvulsant Syndrome (FACS) that Emma realised the children, who all had special needs, had been irreversibly damaged in the womb by the anti-epileptic drugs she had taken since she was 12.
After the scandal of the devastating birth defects caused by the morning-sickness drug Thalidomide in the Fifties, it seems inconceivable that the same situation could occur again. But for thousands of families in the UK, the word Epilim has the same sinister connotations.
It has been prescribed since 1978 and reports of the ingredient sodium valproate causing birth defects such as spina bifida go back almost as far. FACS is believed to have affected up to 20,000 babies – ten times more than Thalidomide.
FACS is thought to be caused in the first three months of pregnancy when an anti-epileptic drug crosses the placenta into the foetus. Effects depend on the dosage and the drug.
There are three FACS syndromes, each involving different anti-epileptic drugs and each with their own set of symptoms. In 2010, Epilim was taken by more than 21,500 women aged between 20 and 39 for epilepsy and other conditions. It is indicated in 80 per cent of cases of FACS.
Dr Peter Turnpenny, clinical geneticist at the Royal Devon and Exeter Hospital, says: ‘Epilim may affect about 560 babies every year, and 10,000 to 20,000 since being introduced to the UK.’
FACS is, Dr Turnpenny points out, less dramatic than the missing and distorted limbs caused by Thalidomide, but the neurological effects are far worse. ‘About ten per cent of foetuses exposed to sodium valproate will have a major congenital malformation such as cleft palate. Twelve per cent are likely to be diagnosed with a neuro-developmental disorder.’
Emma, 31, was prescribed Epilim after developing epilepsy as a girl. She and Joe, 39, a taxi driver, were oblivious to the concerns about the drug.
Their first three children were born prematurely. Within 24 hours they became limp and unresponsive. All had delayed speech and Lauren and Luke were late walkers. Lauren was diagnosed with cerebral palsy aged two.
Emma saw the TV programme on FACS when she was four months pregnant with their youngest daughter Erin, now four. She heard one mother, Janet Williams, describing the symptoms experienced by her two sons who have FACS. ‘I knew straight away,’ Emma says. She contacted the Organisation for Anticonvulsant Syndrome, a support group founded in 1999 by Janet.
Emma’s GP finally referred her to a geneticist who recognised immediately the characteristic facial features in the children – a thin upper lip, small, crowded teeth and wide nasal bridge.
A year later, Emma’s youngest son Kian was conceived – an unplanned pregnancy when Emma took a course of antibiotics that may have reduced the effectiveness of her contraceptive pill. Although Emma immediately changed her Epilim for Keppra, a newer drug with no known links to FACS, it was too late.
All five children have hypermobile joints, which means they are excessively bendy and painful at night. Lauren needs a walking frame and she and Luke have support workers at school. Joe has been forced to give up work because of Emma’s epilepsy and the children’s needs.
Janet Williams, whose sons are now in their 20s, says: ‘I saw my GP and my gynaecologist when I was pregnant and was told to keep taking the Epilim. There wasn’t an information leaflet in the box at that time. I trusted the medical profession.’
Emma agrees. ‘As soon as I found out I was pregnant, I asked my GP whether my medication was safe. Because of the severity of my epilepsy, I was under a team of medics throughout all my pregnancies. I was never warned.’
Both women are calling for anyone prescribing anti-epileptic drugs to warn of the risks during pregnancy.
‘The problem is that Epilim is a very good drug,’ says consultant neurologist Suzanne O’Sullivan at BMI The London Independent Hospital. ‘These days we avoid putting women of childbearing age on it as a first-choice drug. Not all doctors are aware of the risk.’
No one is suggesting that women stop taking their anti-epileptic drugs. ‘Major convulsive seizures could cause injury to the baby or a miscarriage, but there are other effective drugs available that are known to be safe during pregnancy,’ says consultant neurologist Dr Jim Morrow at the Royal Victoria Hospital, Belfast.
‘If you have epilepsy and are considering having children, see your specialist and plan two years in advance as it may take this long to change your drug regime,’ adds Dr O’Sullivan.
If you get pregnant accidentally, we would put you on high-dose folic acid and treat it as a high-risk pregnancy. There’s a good chance the baby will be fine.’ A spokesman for Sanofi, which makes Epilim, says: ‘We have always provided appropriate information and warnings in relation to the potential side effects and risks associated with use of this medicine, including risks to the unborn child, in line with developing scientific knowledge.
‘Sodium valproate remains the most effective treatment of generalised epilepsy. Sanofi has been proactive in supporting ongoing research to evaluate the risk-benefit profile in all patient groups and continues to work closely with the scientific and medical communities.’
But David Body, solicitor at medical specialists Irwin Mitchell, claims the manufacturer did not give adequate warnings in its product leaflets before 1997. In 2006, about 140 affected families launched a case against the manufacturer. It collapsed last year and legal aid was withdrawn as it was thought there was insufficient evidence to win.
Emma doesn’t care about compensation, just that other families are not torn apart. ‘Our lives revolve around caring for the children’s complicated health needs and we don’t know what the future holds,’ she says. ‘I want the medical profession to be educated about it and for women to be in a position to make an informed choice.’
Source : Daily Mail
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Dilantin (phenytoin) Oral Suspension
CONTRAINDICATION - Hypersensitivity to inactive ingredients
Source : FDA
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FDA Drug Safety Communication: Children born to mothers who took Valproate products while pregnant may have impaired cognitive development
Valproate products include: valproate sodium (Depacon), divalproex sodium (Depakote, Depakote CP, and Depakote ER), valproic acid (Depakene and Stavzor), and their generics.
Valproate products are FDA-approved drugs to treat seizures, and manic or mixed episodes associated with bipolar disorder (manic-depressive disorder), and to prevent migraine headaches. They are also used off-label (for unapproved uses) for other conditions, particularly for other psychiatric condition
[6-30-2011] The U.S. Food and Drug Administration (FDA) is informing the public that children born to mothers who take the anti-seizure medication valproate sodium or related products (valproic acid and divalproex sodium) during pregnancy have an increased risk of lower cognitive test scores than children exposed to other anti-seizure medications during pregnancy. This conclusion is based on the results of epidemiologic studies that show that children born to mothers who took valproate sodium or related products throughout their pregnancy tend to score lower on cognitive tests (IQ and other tests) than children born to mothers who took other anti-seizure medications during pregnancy.
In the primary epidemiologic study upon which FDA’s conclusion is based, cognitive tests were performed at age three. In supportive studies, cognitive tests were performed at ages five to 16. Cognitive tests are commonly used to assess development in a variety of areas, including intelligence, abstract reasoning, and problem solving.
The long-term effects on cognitive development from exposure to valproate sodium or related products during pregnancy are unknown. It is also not known whether these effects occur when fetal exposure is limited to less than the full duration of pregnancy, such as the first trimester.
FDA has evaluated all available evidence to date, and will be adding information about the risk of lower cognitive test scores to the valproate product labels in the Warnings and Precautions section, the Use in Specific Populations: Pregnancy section, and to the Medication Guides that are being developed for the valproate drug products.
FDA previously warned pregnant women and women of childbearing age about valproate use during pregnancy due to the known risk of birth defects (teratogenic effects) of these products. A teratogen is anything known to cause birth defects during development of an embryo or fetus. Valproate products are assigned to Pregnancy Category D. FDA released an Information for Healthcare Professionals communication in December 2009 on the risk of neural tube birth defects following exposure to valproate products during pregnancy.
The benefits and the risks of valproate sodium and related products should be carefully weighed when prescribing these drugs to women of childbearing age, particularly for conditions not usually associated with permanent injury or death. If the use of valproate is not essential, alternative medications that have a lower risk to the fetus of birth defects and adverse cognitive effects should be considered in pregnant women and women of childbearing age. If the decision is made to use valproate in women of childbearing age, effective birth control should be used.(See Data Summary).
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary
Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found children with prenatal exposure to valproate throughout pregnancy had lower Differential Ability Scale (D.A.S) scores at age 3 (92 [95% confidence interval 88 to 97]) than children with prenatal exposure to the other evaluated antiepileptic drug monotherapy treatments: lamotrigine (101 [95% confidence interval 98 to 104]), carbamazepine (98 [95% confidence interval 95 to 102]) and phenytoin (99 [95% confidence interval 94 to 104]).1 The D.A.S., which has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children 2.5 to 17 years of age. The D.A.S. is a measure of cognitive development performed in children who are too young to undergo IQ testing, and generally correlates with IQ scores later in childhood. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero causes subsequent adverse effects on cognitive development in offspring.
References
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Pfizer Settles Neurontin Suit Over Minister’s Death
Pfizer Inc. agreed to settle a wrongful-death lawsuit alleging its Neurontin epilepsy medicine caused a retired minister to commit suicide two months after he started taking the drug. Lawyers for New York-based Pfizer, the world’s biggest drugmaker, told a judge in Nashville, Tennessee, they resolved claims by the family of Richard Smith, which were set to go to trial today. It’s the second settlement of claims that officials of a Pfizer unit knew the epilepsy drug posed a suicide risk and failed to disclose it to patients and doctors.
“I’m very pleased the case has been resolved,” U.S. District Judge Aleta Trauger told lawyers for Smith’s family and the company today. The terms weren’t disclosed. Smith, 79, was a retired Church of Christ minister, according to court papers. He was taking the drug to deal with chronic pain, not epilepsy, the filings show.
Pfizer faces more than 1,000 lawsuits accusing it of illegally promoting Neurontin for unapproved uses and helping to cause some users’ suicides. In March, a Boston jury ordered Pfizer to pay more than $140 million in damages to an insurer over its marketing practices in connection with the drug. Pfizer has denied any wrongdoing in connection with its handling of Neurontin.
‘Great Sympathy’
Its Warner-Lambert subsidiary pleaded guilty in 2004 to criminal charges filed by the Justice Department in connection with allegations it illegally marketed Neurontin and paid a $430 million fine. Pfizer bought Warner-Lambert for $120 billion in 2000.
“We are pleased to have reached an agreement with the Smith family to resolve this case as it avoids the time and expense of a trial,” Chris Loder, a Pfizer spokesman, said in an e-mailed statement. “We have great sympathy for the Smith family and respect their desire for privacy regarding the outcome of the case.”
By prescribing Neurontin as a painkiller, Smith’s doctor was recommending a so-called off-label use of the drug. While doctors may prescribe a medicine for uses not approved by the U.S. Food and Drug Administration, companies are barred from promoting products for off-label uses.
As part of the guilty plea, Warner-Lambert officials acknowledged the company engaged in “deceptive off-label marketing” of Neurontin, Maryland Attorney General J. Joseph Curran Jr. said in 2004.
‘Snake-Oil List’
A former Warner-Lambert medical liaison testified in an earlier Neurontin suit he was trained to market the drug to doctors for uses beyond those approved by regulators. Dr. David Franklin, who won a $25 million whistleblower suit against the drugmaker over the medicine, said he was given a “snake-oil list” of unapproved uses to help pump up Neurontin’s sales. Franklin had been set to testify in Smith’s case.
Smith, who worked part-time as a service manager at a Nashville office-machines store, began taking Neurontin in March 2004 to deal with chronic pain tied to back and neck surgeries, according to court filings. Lawyers for his family say in the filings that Warner-Lambert officials didn’t properly warn Smith’s doctors the drug had been found to cause depression and suicidal thoughts in some users.
‘Forgive Me’
In May, Smith killed himself with a gunshot to the head, according to the filings. In a note he left to his family, Smith indicated he was tired of being in pain.
“Forgive me; I cannot go on like this, I cannot have my body, the temple of the Holy Spirit, cut on anymore,” Smith said in the note. “I have talked to God all night and he understands.”
Lawyers for Smith’s family said he’d told relatives prior to his suicide that the Neurontin “was making him feel not himself,” according to court filings. “Mr. Smith’s death was inexplicable to family members because Mr. Smith was a godly man and he knew suicide was wrong,” they added in the filing.
Pfizer’s lawyers countered in their filings Smith suffered through “numerous surgeries” which left him dealing with “increasing pain.” The retired minister told his family he “wished he could die because of the pain and the depression,” the filing added.
The case is Ruby Smith v. Pfizer Inc., 05-cv-11515-PBS, U.S. District Court, Middle District of Tennessee (Nashville).
Source: Bloomberg Businessweek
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Pfizer Agrees to First Neurontin Lawsuit Settlement
Pfizer Inc. agreed to pay about $400,000 to settle a lawsuit mid-trial that blamed its Neurontin epilepsy medicine for helping cause a Massachusetts man’s suicide, two people familiar with the accord said. It’s the first settlement over a Neurontin-related suicide claim. Pfizer, the world’s largest drugmaker, agreed yesterday to resolve allegations by Hartley Shearer’s family in Boston federal court that its Warner-Lambert unit knew the drug posed a suicide risk and failed to disclose it to patients and doctors.
“Pfizer agreed to settle the case for less than its defense costs remaining in this case,” said Rob Haralson, a spokesman for New York-based Pfizer. “Pfizer maintains that it has strong defenses to each of plaintiff’s claims.”
Pfizer faces more than 1,000 lawsuits accusing it of illegally promoting Neurontin for unapproved uses and helping to cause some users’ suicides. The settlement comes a week after another Boston jury ordered Pfizer to pay more than $140 million in damages to an insurer over the drug. Pfizer has denied any wrongdoing in connection with its handling of Neurontin.
Its Warner-Lambert subsidiary pleaded guilty in 2004 to criminal charges filed by the Justice Department in connection with allegations it illegally marketed Neurontin and paid a $430 million fine. Pfizer acquired Warner-Lambert in 2000.
For 16 Months
The 57-year-old Shearer, a part-time lecturer at Williams College in Williamstown, Massachusetts, took Neurontin for 16 months before killing himself, according to court filings.
Shearer’s family contends his doctor wasn’t aware of Neurontin’s suicide risk when he prescribed the drug to help deal with pain generated by a 1999 stroke.
Pfizer argued Shearer battled depression for most of his life and was taking a dozen prescription drugs, including an anti-depressant, when he shot himself to death with a .357 Magnum handgun in 2002.
The drugmaker’s lawyers also noted Shearer argued with his wife the day he killed himself and left a suicide note saying it was the last time she would “leave me powerless.”
Ron Rosenkranz, a lawyer for the Shearers, declined to comment when contacted yesterday evening. Today, he told U.S. District Judge William G. Young at a hearing in Boston that the “amount of the settlement, while confidential, is substantially less than the amount reported.”
‘An Iffy Case’
“This is an iffy case,” Young told jurors after announcing the accord. “This is why they settled. Iffy on both sides.” The people who said the settlement was about $400,000 declined to be identified because the terms are confidential.
By prescribing Neurontin as a painkiller, Shearer’s doctor was recommending a so-called off-label use of the drug. While doctors may prescribe a medicine for uses not approved by the U.S. Food and Drug Administration, companies are barred from promoting products for off-label uses.
Dr. Charles King, a former Harvard University business professor, told jurors in the Shearer case yesterday that Warner-Lambert officials used illegal off-label marketing tactics to turn Neurontin into a “blockbuster drug.”
“They took a drug that was expected to generate $500 million over its lifetime and turned it into a drug that sold roughly $10 billion,” said King, an economist who testified for the Shearers as an expert on pharmaceutical- industry marketing practices.
The Shearer suit was the second product-liability case over Neurontin to go to trial.
In July 2009, a Peabody, Massachusetts, family dropped its suit over the suicide of a woman who was taking the drug. The family was in the second day of trial in federal court in Boston when it decided to dismiss the case.
Misleading Doctors
Another jury in Boston’s federal court March 25 said Pfizer must pay Kaiser Foundation Health Plan Inc. $47.4 million for misleading doctors on whether Neurontin was effective for illnesses such as migraines and bipolar disorder.
The jury found the drugmaker violated the federal Racketeer Influenced and Corrupt Organizations Act, or RICO, and California’s Unfair Competition Law.
The Oakland, California-based insurer is a unit of Kaiser Permanente, the largest U.S. nonprofit health maintenance organization. Under RICO, the amount of actual damages will be tripled to $142.1 million.
Pfizer bought Warner-Lambert for $120 billion in 2000 and Pharmacia for $54 billion three years later.
$430 Million Settlement
Along with the $430 million settlement of allegations over Neurontin, Pfizer also paid $2.3 billion in October 2009 to resolve U.S. Justice Department allegations it illegally marketed the painkiller Bextra and three other drugs.
“When you acquire Warner-Lambert you get Neurontin, and when you acquire Pharmacia you get Bextra, and some of these problems came with the acquisitions,” Jeffrey Kindler, Pfizer’s chief executive officer told the New York Times March 31. “It doesn’t change the facts or our responsibility for them.”
The Shearer case is Shearer v. Pfizer Inc., 07-cv-11428- PBS, U.S. District Court, District of Massachusetts (Boston).
Source:Bloomberg Businessweek
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Pfizer to pay $142M for drug fraud
- Neurontin
Sales of drug total $300M annually in Canada
Pharmaceutical giant Pfizer has been ordered to pay $142 million US in damages for fraudulently marketing gabapentin, an anti-seizure drug marketed under the name Neurontin.
A federal jury in Boston ruled Thursday that Pfizer fraudulently marketed the drug and promoted it for unapproved uses. The jury sided with California-based Kaiser Foundation Health Plan Inc. and Kaiser Foundation Hospitals, the first to try a gabapentin case against Pfizer.
Data revealed in a string of U.S. lawsuits indicates the drug was promoted by the drug company as a treatment for pain, migraines and bipolar disorder — even though it wasn't effective in treating these conditions and was actually toxic in certain cases, according to the Therapautics Initiative, an independent drug research group at the University of British Columbia.
The trials forced the company to release all of its studies on the drug, including the ones it kept hidden.
A new analysis of those unpublished trials by the Therapeutics Initiative suggests that gabapentin works for one out of every six or eight people who use it, at best. The review also concluded that one in eight people had an adverse reaction to the drug.
"The much larger majority of people will not get any benefit and many of them will have chronic neurotoxicity or poisoning of the brain," said Dr. Tom Perry of the Therapeutics Initiative.
Dr. Harry Pollett, a pain specialist in North Sydney, N.S., calls gabapentin a so-so drug with potentially serious side-effects for patients. These include drowsiness, balance problems, fogginess and edema, or swelling.
"Weight gain is a very common problem and I see that a lot," Pollett said.
The drugs represent a waste of money for Canada's health-care system, said Perry, who questioned why some doctors continue to encourage people to take the drug even though the patients are not benefiting.
"We have been using probably somewhere in the order of around $300 million a year in Canada recently and this drug has been overused since the late 1990s," Perry said. "So, do the math. It's probably well in excess of a billion dollars."
Pfizer defends its actions and its drug. The company has already been hit with $430 million in penalties and fines for fraudulently promoting gabapentin in the U.S.
SOURCE: CBS NEWS
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Potiga (ezogabine): Drug Safety Communication - FDA Determines 2013 Labeling Adequate to Manage Risks of Retinal Abnormalities, Potential Vision Loss, and Skin Discoloration
AUDIENCE: Neurology, Eye Care, Dermatology
ISSUE: Based on reviews of additional safety reports from patients treated with the anti-seizure drug Potiga (ezogabine), the FDA has determined that the potential risks of vision loss due to pigment changes in the retina and of skin discoloration can be adequately managed by following the current recommendations in the Potiga labeling. To further explore any potential long-term consequences of these pigment changes, FDA has required the Potiga manufacturer, GlaxoSmithKline, to conduct a long-term observational study.
FDA review of additional safety reports does not indicate that the pigment changes in the retina observed in some patients affect vision. Skin discoloration associated with the use of Potiga appears to be a cosmetic effect and does not appear to be associated with more serious adverse effects. Therefore, a modification of the Risk Evaluation and Mitigation Strategy (REMS) is not needed at this time to ensure that the benefits of Potiga outweigh the risks of retinal and skin pigment changes. FDA expects that the required long-term observational study will provide further information on whether pigment changes in the retina caused by Potiga can lead to vision loss or other long-term side effects. In addition, the study should provide more information on the relationship between pigment changes in the retina and skin discoloration.
BACKGROUND: Potiga is approved for use in combination with other anti-seizure drugs to treat partial-onset seizures in adult patients who have had an inadequate response to several alternative therapies and for whom the benefits of treatment outweigh the risks.
RECOMMENDATION: Health care professionals should continue to follow the recommendations provided in the Boxed Warning, FDA’s most serious type of warning, and the Warnings and Precautions and Indications and Usage sections of the labeling.
Source : FDA (June 2015)
FDA Drug Safety Communication: FDA warns of serious skin reactions with the anti-seizure drug Onfi (clobazam) and has approved label changes
The U.S. Food and Drug Administration (FDA) is warning the public that the anti-seizure drug Onfi (clobazam) can cause rare but serious skin reactions that can result in permanent harm and death. We have approved changes to the Onfi drug label and the patient Medication Guide to describe the risk of these serious skin reactions. Patients taking Onfi should seek immediate medical treatment if they develop a rash, blistering or peeling of the skin, sores in the mouth, or hives. Health care professionals should discontinue use of Onfi and consider an alternate therapy at the first sign of rash, unless it is clearly not drug-related. These rare but serious skin reactions, called Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), can occur at any time during Onfi treatment. However, the likelihood of skin reactions is greater during the first 8 weeks of treatment or when Onfi is stopped and then re-started. All cases of SJS and TEN in the FDA case series have resulted in hospitalization, one case resulted in blindness, and one case resulted in death.
Onfi is a benzodiazepine medication used in combination with other medicines to treat seizures associated with a severe form of epilepsy called Lennox-Gastaut Syndrome. Serious skin reactions have not generally been associated with other benzodiazepines.
Patients should not stop taking Onfi without first talking to their health care professionals. Stopping Onfi suddenly can cause serious withdrawal problems, such as seizures that will not stop, hallucinations (hearing or seeing things that are not real), shaking, nervousness, and stomach or muscle cramps.
Source : FDA (Dec. 2013)
FDA Drug Safety Communication: Valproate Anti-seizure Products Contraindicated for Migraine Prevention in Pregnant Women due to Decreased IQ Scores in Exposed Children
The U.S. Food and Drug Administration (FDA) is advising health care professionals and women that the anti-seizure medication valproate sodium and related products, valproic acid and divalproex sodium, are contraindicated and should not be taken by pregnant women for the prevention of migraine headaches. Based on information from a recent study, there is evidence that these medications can cause decreased IQ scores in children whose mothers took them while pregnant.1 Stronger warnings about use during pregnancy will be added to the drug labels, and valproate’s pregnancy category for migraine use will be changed from "D" (the potential benefit of the drug in pregnant women may be acceptable despite its potential risks) to "X" (the risk of use in pregnant women clearly outweighs any possible benefit of the drug).With regard to valproate use in pregnant women with epilepsy or bipolar disorder, valproate products should only be prescribed if other medications are not effective in treating the condition or are otherwise unacceptable. Valproate products will remain in pregnancy category D for treating epilepsy and manic episodes associated with bipolar disorder.
With regard to women of childbearing age who are not pregnant, valproate should not be taken for any condition unless the drug is essential to the management of the woman's medical condition. All non-pregnant women of childbearing age taking valproate products should use effective birth control.
Valproate products include: valproate sodium (Depacon), divalproex sodium (Depakote, Depakote CP, and Depakote ER), valproic acid (Depakene and Stavzor), and their generics.
This alert is based on the final results of the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study showing that children exposed to valproate products while their mothers were pregnant had decreased IQs at age 6 compared to children exposed to other anti-epileptic drugs (see Data Summary).1 The difference in average IQ between the children who had been exposed to valproate and the children who had been exposed to other antiepileptic drugs varied between 8 and 11 points depending on the drug to which valproate was compared.
FDA previously communicated initial findings about this risk in a June 2011 Drug Safety Communication. At that time, FDA also worked with valproate manufacturers to revise the drug labels after interim results from the NEAD study showed lower cognitive test scores at age 3 in children exposed to valproate compared to children exposed to other antiepileptic drugs.2
Women who are pregnant and taking a valproate medication should not stop their medication but should talk to their health care professionals immediately. Stopping valproate treatment suddenly can cause serious and life-threatening medical problems to the woman or her baby.
It is not known whether there is a specific time period during pregnancy when valproate exposure can result in negative cognitive effects. Similarly, there is no known time during pregnancy in which exposure may be considered to have less risk for decreased IQ in children. Because the women in the NEAD study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed.
FDA is working with manufacturers to change the drug labels for valproate products with this updated risk information. FDA continues to evaluate information about the potential risks of valproate use during pregnancy and will update the public as more information becomes available.
Pregnancy Category X means that studies in animals or humans have shown positive evidence of fetal risk, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefits. Category D means there is positive evidence of risk to a baby based on data from studies or other experience in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.
Source : FDA (May 2013)
Potiga (Ezogabine): Drug Safety Communication - Linked To Retinal Abnormalities And Blue Skin Discoloration
ISSUE: FDA is warning the public that the anti-seizure medication Potiga (Ezogabine) can cause blue skin discoloration and eye abnormalities characterized by pigment changes in the retina. FDA does not currently know if these changes are reversible. FDA is working with the manufacturer to gather and evaluate all available information to better understand these events. FDA will update the public when more information is available.
BACKGROUND: Potiga is approved as adjunctive (added on to other anti-seizure medications) treatment of partial-onset seizures in adult patients 18 years and older. The skin discoloration in the reported cases appeared as blue pigmentation, predominantly on or around the lips or in the nail beds of the fingers or toes, but more widespread involvement of the face and legs has also been reported. Scleral and conjunctival discoloration, on the white of the eye and inside eyelids, has been observed as well. The skin discoloration generally occurred after four years of treatment with Potiga, but has appeared sooner in some patients. In some cases, retinal abnormalities have been observed in the absence of skin discoloration.
RECOMMENDATION: All patients taking Potiga should have a baseline eye exam and periodic eye exams that should include visual acuity testing and dilated fundus photography, and may include fluorescein angiograms (FA), ocular coherence tomography (OCT), perimetry, and electroretinograms (ERG). Patients who are taking Potiga and develop any changes in your vision or any discoloration of your skin, including of your lips and nail beds should contact their health care professional right away. Patients should not stop taking Potiga without talking to their health care professional. Stopping such treatment suddenly can cause serious and life-threatening medical problems such as recurrence of seizures.
Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety
Source - FDA Safety Communication - FDA]
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Epilepsy drug in pregnancy tied to autism risk
Women who take the epilepsy drug valproate during pregnancy are three times more likely to have a child with an autism spectrum disorder, suggests new research based on close to 700,000 babies born in Denmark.
Previous studies have found more birth defects and lower intelligence among children of mothers who took valproate, but the new work represents the "strongest evidence to date" of a link between the drug and autism, according to an editorial published with the study on Tuesday.
The results don't prove the generic drug, also sold as valproic acid, causes autism. But researchers were able to account for a number of underlying factors - such as the age and health of the mothers and the babies' fathers - that make the study more convincing, Christopher Stodgell said.
"This finding isn't necessarily a brand new finding, but it's an important finding in that (researchers studied) really a much larger population, and they also looked at some other underlying drivers," said Stodgell, who studies the origins of autism at the University of Rochester Medical Center but wasn't involved in the new research.
Women "need to be very diligent about what the effects are if they're taking valproic acid," he told Reuters Health.
About one in 88 children has an autism spectrum disorder, or ASD, according to the U.S. Centers for Disease Control and Prevention. Those conditions range from autism itself to less disabling ones such as Asperger's syndrome.
For the new study, researchers tracked 656,000 kids born in Denmark between 1996 and 2006. Using a large prescription drug database, they found that just under 6,600 of the mothers of those children had epilepsy and 508 women took valproate while pregnant.
By 2010, 4.4 percent of the kids whose mothers had taken valproate during pregnancy were diagnosed with any ASD, including 2.5 percent with autism.
In contrast, 1.5 percent of all babies in the study had an ASD and 0.5 percent had autism, the study team reported in the Journal of the American Medical Association.
Mothers' underlying epilepsy didn't fully explain the link, according to Jakob Christensen from Aarhus University and his colleagues. In addition, autism rates were higher among children of women who used valproate during pregnancy than those who had previously used the drug but stopped before conceiving.
CONSIDER RISKS, BENEFITS
"Valproate is an effective drug, but it appears that it is being prescribed for women of childbearing potential at a rate that does not fully consider the ratio of benefits to risks," wrote Dr. Kimford Meador and David Loring from Emory University in Atlanta, in a linked editorial.
Valproate could affect maturation of a fetus's brain, Christensen suggested, including the signal-sending neurotransmitters.
Women who may become pregnant "certainly should discuss with their doctor if there are alternative treatments that would be reasonable," he told Reuters Health.
For those with certain syndromes or generalized epilepsy, there aren't necessarily other good options. Stopping valproate in that case isn't a good idea, Christensen said.
"It's also a risk if you have seizures, both for the mother and the unborn child. (Stopping medication) is not a thing that you take lightly," he said.
"Even those that are exposed to this drug, there's still a good chance - more than a 95-percent chance - that their child will never develop signs of autism."
The study didn't take into account whether women drank during pregnancy, or if they took folic acid - which has been tied to a lower risk of some birth defects.
Christensen said there are steps pregnant women on valproate can take to lower any risks to their baby, such as using the lowest possible dose and dividing it up during the day.
Source : Reuters via bit.ly/JjFzqx Journal of the American Medical Association, online April 23, 2013.
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Why are doctors still not warning about the 'new Thalidomide'? Mother tells how taking an anti-epileptic drug while pregnant devastated the heath of two of her children
In 2008, Emma Murphy phoned her partner Joe at work. ‘I know what’s wrong with the children,’ she said.
For four years the couple had been perplexed by the health problems that affected their daughters Chloe and Lauren and their son Luke – and their GP had consistently dismissed their concerns.
It was only after watching a television programme about Fetal Anticonvulsant Syndrome (FACS) that Emma realised the children, who all had special needs, had been irreversibly damaged in the womb by the anti-epileptic drugs she had taken since she was 12.
After the scandal of the devastating birth defects caused by the morning-sickness drug Thalidomide in the Fifties, it seems inconceivable that the same situation could occur again. But for thousands of families in the UK, the word Epilim has the same sinister connotations.
It has been prescribed since 1978 and reports of the ingredient sodium valproate causing birth defects such as spina bifida go back almost as far. FACS is believed to have affected up to 20,000 babies – ten times more than Thalidomide.
FACS is thought to be caused in the first three months of pregnancy when an anti-epileptic drug crosses the placenta into the foetus. Effects depend on the dosage and the drug.
There are three FACS syndromes, each involving different anti-epileptic drugs and each with their own set of symptoms. In 2010, Epilim was taken by more than 21,500 women aged between 20 and 39 for epilepsy and other conditions. It is indicated in 80 per cent of cases of FACS.
Dr Peter Turnpenny, clinical geneticist at the Royal Devon and Exeter Hospital, says: ‘Epilim may affect about 560 babies every year, and 10,000 to 20,000 since being introduced to the UK.’
FACS is, Dr Turnpenny points out, less dramatic than the missing and distorted limbs caused by Thalidomide, but the neurological effects are far worse. ‘About ten per cent of foetuses exposed to sodium valproate will have a major congenital malformation such as cleft palate. Twelve per cent are likely to be diagnosed with a neuro-developmental disorder.’
Emma, 31, was prescribed Epilim after developing epilepsy as a girl. She and Joe, 39, a taxi driver, were oblivious to the concerns about the drug.
Their first three children were born prematurely. Within 24 hours they became limp and unresponsive. All had delayed speech and Lauren and Luke were late walkers. Lauren was diagnosed with cerebral palsy aged two.
Emma saw the TV programme on FACS when she was four months pregnant with their youngest daughter Erin, now four. She heard one mother, Janet Williams, describing the symptoms experienced by her two sons who have FACS. ‘I knew straight away,’ Emma says. She contacted the Organisation for Anticonvulsant Syndrome, a support group founded in 1999 by Janet.
Emma’s GP finally referred her to a geneticist who recognised immediately the characteristic facial features in the children – a thin upper lip, small, crowded teeth and wide nasal bridge.
A year later, Emma’s youngest son Kian was conceived – an unplanned pregnancy when Emma took a course of antibiotics that may have reduced the effectiveness of her contraceptive pill. Although Emma immediately changed her Epilim for Keppra, a newer drug with no known links to FACS, it was too late.
All five children have hypermobile joints, which means they are excessively bendy and painful at night. Lauren needs a walking frame and she and Luke have support workers at school. Joe has been forced to give up work because of Emma’s epilepsy and the children’s needs.
Janet Williams, whose sons are now in their 20s, says: ‘I saw my GP and my gynaecologist when I was pregnant and was told to keep taking the Epilim. There wasn’t an information leaflet in the box at that time. I trusted the medical profession.’
Emma agrees. ‘As soon as I found out I was pregnant, I asked my GP whether my medication was safe. Because of the severity of my epilepsy, I was under a team of medics throughout all my pregnancies. I was never warned.’
Both women are calling for anyone prescribing anti-epileptic drugs to warn of the risks during pregnancy.
‘The problem is that Epilim is a very good drug,’ says consultant neurologist Suzanne O’Sullivan at BMI The London Independent Hospital. ‘These days we avoid putting women of childbearing age on it as a first-choice drug. Not all doctors are aware of the risk.’
No one is suggesting that women stop taking their anti-epileptic drugs. ‘Major convulsive seizures could cause injury to the baby or a miscarriage, but there are other effective drugs available that are known to be safe during pregnancy,’ says consultant neurologist Dr Jim Morrow at the Royal Victoria Hospital, Belfast.
‘If you have epilepsy and are considering having children, see your specialist and plan two years in advance as it may take this long to change your drug regime,’ adds Dr O’Sullivan.
If you get pregnant accidentally, we would put you on high-dose folic acid and treat it as a high-risk pregnancy. There’s a good chance the baby will be fine.’ A spokesman for Sanofi, which makes Epilim, says: ‘We have always provided appropriate information and warnings in relation to the potential side effects and risks associated with use of this medicine, including risks to the unborn child, in line with developing scientific knowledge.
‘Sodium valproate remains the most effective treatment of generalised epilepsy. Sanofi has been proactive in supporting ongoing research to evaluate the risk-benefit profile in all patient groups and continues to work closely with the scientific and medical communities.’
But David Body, solicitor at medical specialists Irwin Mitchell, claims the manufacturer did not give adequate warnings in its product leaflets before 1997. In 2006, about 140 affected families launched a case against the manufacturer. It collapsed last year and legal aid was withdrawn as it was thought there was insufficient evidence to win.
Emma doesn’t care about compensation, just that other families are not torn apart. ‘Our lives revolve around caring for the children’s complicated health needs and we don’t know what the future holds,’ she says. ‘I want the medical profession to be educated about it and for women to be in a position to make an informed choice.’
Source : Daily Mail
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Dilantin (phenytoin) Oral Suspension
CONTRAINDICATION - Hypersensitivity to inactive ingredients
- Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.
- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively ….
- The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. ...
- Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes
- Drugs that should not be used concurrently with phenytoin: Delavirdine.
- Drugs which may increase phenytoin serum levels include: fluvoxamine,fluorouracil, omeprazole, sertraline, warfarin.
- Drugs that may decrease plasma phenytoin concentrations include nelfinavir, ritonavir
- Drugs whose efficacy is impaired by phenytoin include: azoles (ketoconazole, itraconazole, voriconazole),sertraline,teniposide,irinotecan,paclitaxel, warfarin
- Phenytoin decreases plasma concentrations of certain HIV antivirals (amprenavir, efavirenz,Kaletra(lopinavir/ritonavir), indinavir, nelfinavir, ritonavir, saquinavir), and anti-epileptic agents (felbamate, topiramate, oxcarbazepine, quetiapine). Addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents
- Body as a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see Warnings section) have been observed. Anaphylaxis has also been reported.
- There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and mmunoglobulin abnormalities.
- Central Nervous System: paresthesia, somnolence,
- Digestive System: enlargement of the lips, gingival hyperplasia,
- Skin and Appendages:There have also been reports of hypertrichosis.
- Special Senses: Altered taste sensation including metallic taste.
- Urogenital: Peyronie’s disease
Source : FDA
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FDA Drug Safety Communication: Children born to mothers who took Valproate products while pregnant may have impaired cognitive development
Valproate products include: valproate sodium (Depacon), divalproex sodium (Depakote, Depakote CP, and Depakote ER), valproic acid (Depakene and Stavzor), and their generics.
Valproate products are FDA-approved drugs to treat seizures, and manic or mixed episodes associated with bipolar disorder (manic-depressive disorder), and to prevent migraine headaches. They are also used off-label (for unapproved uses) for other conditions, particularly for other psychiatric condition
[6-30-2011] The U.S. Food and Drug Administration (FDA) is informing the public that children born to mothers who take the anti-seizure medication valproate sodium or related products (valproic acid and divalproex sodium) during pregnancy have an increased risk of lower cognitive test scores than children exposed to other anti-seizure medications during pregnancy. This conclusion is based on the results of epidemiologic studies that show that children born to mothers who took valproate sodium or related products throughout their pregnancy tend to score lower on cognitive tests (IQ and other tests) than children born to mothers who took other anti-seizure medications during pregnancy.
In the primary epidemiologic study upon which FDA’s conclusion is based, cognitive tests were performed at age three. In supportive studies, cognitive tests were performed at ages five to 16. Cognitive tests are commonly used to assess development in a variety of areas, including intelligence, abstract reasoning, and problem solving.
The long-term effects on cognitive development from exposure to valproate sodium or related products during pregnancy are unknown. It is also not known whether these effects occur when fetal exposure is limited to less than the full duration of pregnancy, such as the first trimester.
FDA has evaluated all available evidence to date, and will be adding information about the risk of lower cognitive test scores to the valproate product labels in the Warnings and Precautions section, the Use in Specific Populations: Pregnancy section, and to the Medication Guides that are being developed for the valproate drug products.
FDA previously warned pregnant women and women of childbearing age about valproate use during pregnancy due to the known risk of birth defects (teratogenic effects) of these products. A teratogen is anything known to cause birth defects during development of an embryo or fetus. Valproate products are assigned to Pregnancy Category D. FDA released an Information for Healthcare Professionals communication in December 2009 on the risk of neural tube birth defects following exposure to valproate products during pregnancy.
The benefits and the risks of valproate sodium and related products should be carefully weighed when prescribing these drugs to women of childbearing age, particularly for conditions not usually associated with permanent injury or death. If the use of valproate is not essential, alternative medications that have a lower risk to the fetus of birth defects and adverse cognitive effects should be considered in pregnant women and women of childbearing age. If the decision is made to use valproate in women of childbearing age, effective birth control should be used.(See Data Summary).
Additional Information for Patients
- Valproate should not be stopped without talking to a healthcare professional, even in pregnant women. Stopping valproate suddenly can cause serious problems. Not treating epilepsy or bipolar disorder (manic-depressive disorder) during pregnancy can be harmful to women and their developing babies.
- If you take valproate during pregnancy, know that there is a higher risk that your child may have birth defects or may score lower on cognitive tests (tests that measure mental ability and capacity, such as IQ tests) in childhood than if you use another anti-seizure medicine during pregnancy.
- Women of childbearing age who decide to take valproate should use effective birth control (contraception) while taking the drug. Women should talk to their healthcare professionals about the best kind of birth control to use while taking valproate.
- Before you start valproate, you should tell your healthcare professional if you are pregnant or are planning to become pregnant. Healthcare professionals may discuss other treatment options with you.
- You should tell your healthcare professional right away if you become pregnant while taking valproate. You and your healthcare provider should decide if you should continue to take valproate while you are pregnant.
- If you become pregnant while taking valproate, you should talk to your healthcare professional about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect additional information about the safety of antiepileptic drugs during pregnancy. Information about the North American Drug Pregnancy Registry can be found at http://www.massgeneral.org/aed/.
- If you took valproate while pregnant, let your child’s pediatrician know.
- Valproate passes into breast milk, but its effects on developing babies remain unknown. You should talk to your healthcare professional about the best way to feed your baby if you take valproate.
- You should report any side effects you experience to the FDA MedWatch program using the information in the “Contact Us” box at the bottom of the page.
Additional Information for Healthcare Professionals
- Inform women of childbearing age of the increased risk for adverse effects on cognitive development with prenatal valproate exposure.
- Continue to counsel women of childbearing potential taking valproate about the increased risk of major malformations, including neural tube defects, when valproate is used during pregnancy.
- Weigh the benefits and risks of valproate when prescribing this drug to women of childbearing age, particularly when treating a condition not usually associated with permanent injury or death. Alternative medications that have a lower risk of adverse birth outcomes should be considered. Healthcare professionals should discuss the relative risks and benefits of appropriate alternative therapies.
- Untreated or inadequately treated epilepsy or bipolar disorder during pregnancy increases the risk of complications in both the pregnant mother and her developing baby.
- If the decision is made to prescribe valproate to women of childbearing age, healthcare professionals should recommend use of effective contraception for women who are not planning a pregnancy.
- Inform patients of the North American Antiepileptic Drug (NAAED) Pregnancy Registry and encourage patients who become pregnant to enroll by calling 1-888-233-2334.
- Report adverse events involving valproate to the FDA MedWatch program, using the information in the “Contact Us” box at the bottom of the page.
Data Summary
Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found children with prenatal exposure to valproate throughout pregnancy had lower Differential Ability Scale (D.A.S) scores at age 3 (92 [95% confidence interval 88 to 97]) than children with prenatal exposure to the other evaluated antiepileptic drug monotherapy treatments: lamotrigine (101 [95% confidence interval 98 to 104]), carbamazepine (98 [95% confidence interval 95 to 102]) and phenytoin (99 [95% confidence interval 94 to 104]).1 The D.A.S., which has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children 2.5 to 17 years of age. The D.A.S. is a measure of cognitive development performed in children who are too young to undergo IQ testing, and generally correlates with IQ scores later in childhood. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero causes subsequent adverse effects on cognitive development in offspring.
References
- Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360:1597-605.
- Gaily E, Kantola-Sorsa E, Hiilesmaa V, et al. Normal intelligence in children with prenatal exposure to carbamazepine. Neurology 2004;62:28-32.
- Adab N, Jacoby AD, Chadwick D. Additional educational needs of children born to mothers with epilepsy. J Neuro Neurosurg Psychiatry 2001;70:15-21.
- Adab N, Kini U, Vinten J, et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004;75:1575–83.
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Pfizer Settles Neurontin Suit Over Minister’s Death
Pfizer Inc. agreed to settle a wrongful-death lawsuit alleging its Neurontin epilepsy medicine caused a retired minister to commit suicide two months after he started taking the drug. Lawyers for New York-based Pfizer, the world’s biggest drugmaker, told a judge in Nashville, Tennessee, they resolved claims by the family of Richard Smith, which were set to go to trial today. It’s the second settlement of claims that officials of a Pfizer unit knew the epilepsy drug posed a suicide risk and failed to disclose it to patients and doctors.
“I’m very pleased the case has been resolved,” U.S. District Judge Aleta Trauger told lawyers for Smith’s family and the company today. The terms weren’t disclosed. Smith, 79, was a retired Church of Christ minister, according to court papers. He was taking the drug to deal with chronic pain, not epilepsy, the filings show.
Pfizer faces more than 1,000 lawsuits accusing it of illegally promoting Neurontin for unapproved uses and helping to cause some users’ suicides. In March, a Boston jury ordered Pfizer to pay more than $140 million in damages to an insurer over its marketing practices in connection with the drug. Pfizer has denied any wrongdoing in connection with its handling of Neurontin.
‘Great Sympathy’
Its Warner-Lambert subsidiary pleaded guilty in 2004 to criminal charges filed by the Justice Department in connection with allegations it illegally marketed Neurontin and paid a $430 million fine. Pfizer bought Warner-Lambert for $120 billion in 2000.
“We are pleased to have reached an agreement with the Smith family to resolve this case as it avoids the time and expense of a trial,” Chris Loder, a Pfizer spokesman, said in an e-mailed statement. “We have great sympathy for the Smith family and respect their desire for privacy regarding the outcome of the case.”
By prescribing Neurontin as a painkiller, Smith’s doctor was recommending a so-called off-label use of the drug. While doctors may prescribe a medicine for uses not approved by the U.S. Food and Drug Administration, companies are barred from promoting products for off-label uses.
As part of the guilty plea, Warner-Lambert officials acknowledged the company engaged in “deceptive off-label marketing” of Neurontin, Maryland Attorney General J. Joseph Curran Jr. said in 2004.
‘Snake-Oil List’
A former Warner-Lambert medical liaison testified in an earlier Neurontin suit he was trained to market the drug to doctors for uses beyond those approved by regulators. Dr. David Franklin, who won a $25 million whistleblower suit against the drugmaker over the medicine, said he was given a “snake-oil list” of unapproved uses to help pump up Neurontin’s sales. Franklin had been set to testify in Smith’s case.
Smith, who worked part-time as a service manager at a Nashville office-machines store, began taking Neurontin in March 2004 to deal with chronic pain tied to back and neck surgeries, according to court filings. Lawyers for his family say in the filings that Warner-Lambert officials didn’t properly warn Smith’s doctors the drug had been found to cause depression and suicidal thoughts in some users.
‘Forgive Me’
In May, Smith killed himself with a gunshot to the head, according to the filings. In a note he left to his family, Smith indicated he was tired of being in pain.
“Forgive me; I cannot go on like this, I cannot have my body, the temple of the Holy Spirit, cut on anymore,” Smith said in the note. “I have talked to God all night and he understands.”
Lawyers for Smith’s family said he’d told relatives prior to his suicide that the Neurontin “was making him feel not himself,” according to court filings. “Mr. Smith’s death was inexplicable to family members because Mr. Smith was a godly man and he knew suicide was wrong,” they added in the filing.
Pfizer’s lawyers countered in their filings Smith suffered through “numerous surgeries” which left him dealing with “increasing pain.” The retired minister told his family he “wished he could die because of the pain and the depression,” the filing added.
The case is Ruby Smith v. Pfizer Inc., 05-cv-11515-PBS, U.S. District Court, Middle District of Tennessee (Nashville).
Source: Bloomberg Businessweek
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Pfizer Agrees to First Neurontin Lawsuit Settlement
Pfizer Inc. agreed to pay about $400,000 to settle a lawsuit mid-trial that blamed its Neurontin epilepsy medicine for helping cause a Massachusetts man’s suicide, two people familiar with the accord said. It’s the first settlement over a Neurontin-related suicide claim. Pfizer, the world’s largest drugmaker, agreed yesterday to resolve allegations by Hartley Shearer’s family in Boston federal court that its Warner-Lambert unit knew the drug posed a suicide risk and failed to disclose it to patients and doctors.
“Pfizer agreed to settle the case for less than its defense costs remaining in this case,” said Rob Haralson, a spokesman for New York-based Pfizer. “Pfizer maintains that it has strong defenses to each of plaintiff’s claims.”
Pfizer faces more than 1,000 lawsuits accusing it of illegally promoting Neurontin for unapproved uses and helping to cause some users’ suicides. The settlement comes a week after another Boston jury ordered Pfizer to pay more than $140 million in damages to an insurer over the drug. Pfizer has denied any wrongdoing in connection with its handling of Neurontin.
Its Warner-Lambert subsidiary pleaded guilty in 2004 to criminal charges filed by the Justice Department in connection with allegations it illegally marketed Neurontin and paid a $430 million fine. Pfizer acquired Warner-Lambert in 2000.
For 16 Months
The 57-year-old Shearer, a part-time lecturer at Williams College in Williamstown, Massachusetts, took Neurontin for 16 months before killing himself, according to court filings.
Shearer’s family contends his doctor wasn’t aware of Neurontin’s suicide risk when he prescribed the drug to help deal with pain generated by a 1999 stroke.
Pfizer argued Shearer battled depression for most of his life and was taking a dozen prescription drugs, including an anti-depressant, when he shot himself to death with a .357 Magnum handgun in 2002.
The drugmaker’s lawyers also noted Shearer argued with his wife the day he killed himself and left a suicide note saying it was the last time she would “leave me powerless.”
Ron Rosenkranz, a lawyer for the Shearers, declined to comment when contacted yesterday evening. Today, he told U.S. District Judge William G. Young at a hearing in Boston that the “amount of the settlement, while confidential, is substantially less than the amount reported.”
‘An Iffy Case’
“This is an iffy case,” Young told jurors after announcing the accord. “This is why they settled. Iffy on both sides.” The people who said the settlement was about $400,000 declined to be identified because the terms are confidential.
By prescribing Neurontin as a painkiller, Shearer’s doctor was recommending a so-called off-label use of the drug. While doctors may prescribe a medicine for uses not approved by the U.S. Food and Drug Administration, companies are barred from promoting products for off-label uses.
Dr. Charles King, a former Harvard University business professor, told jurors in the Shearer case yesterday that Warner-Lambert officials used illegal off-label marketing tactics to turn Neurontin into a “blockbuster drug.”
“They took a drug that was expected to generate $500 million over its lifetime and turned it into a drug that sold roughly $10 billion,” said King, an economist who testified for the Shearers as an expert on pharmaceutical- industry marketing practices.
The Shearer suit was the second product-liability case over Neurontin to go to trial.
In July 2009, a Peabody, Massachusetts, family dropped its suit over the suicide of a woman who was taking the drug. The family was in the second day of trial in federal court in Boston when it decided to dismiss the case.
Misleading Doctors
Another jury in Boston’s federal court March 25 said Pfizer must pay Kaiser Foundation Health Plan Inc. $47.4 million for misleading doctors on whether Neurontin was effective for illnesses such as migraines and bipolar disorder.
The jury found the drugmaker violated the federal Racketeer Influenced and Corrupt Organizations Act, or RICO, and California’s Unfair Competition Law.
The Oakland, California-based insurer is a unit of Kaiser Permanente, the largest U.S. nonprofit health maintenance organization. Under RICO, the amount of actual damages will be tripled to $142.1 million.
Pfizer bought Warner-Lambert for $120 billion in 2000 and Pharmacia for $54 billion three years later.
$430 Million Settlement
Along with the $430 million settlement of allegations over Neurontin, Pfizer also paid $2.3 billion in October 2009 to resolve U.S. Justice Department allegations it illegally marketed the painkiller Bextra and three other drugs.
“When you acquire Warner-Lambert you get Neurontin, and when you acquire Pharmacia you get Bextra, and some of these problems came with the acquisitions,” Jeffrey Kindler, Pfizer’s chief executive officer told the New York Times March 31. “It doesn’t change the facts or our responsibility for them.”
The Shearer case is Shearer v. Pfizer Inc., 07-cv-11428- PBS, U.S. District Court, District of Massachusetts (Boston).
Source:Bloomberg Businessweek
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Pfizer to pay $142M for drug fraud
- Neurontin
Sales of drug total $300M annually in Canada
Pharmaceutical giant Pfizer has been ordered to pay $142 million US in damages for fraudulently marketing gabapentin, an anti-seizure drug marketed under the name Neurontin.
A federal jury in Boston ruled Thursday that Pfizer fraudulently marketed the drug and promoted it for unapproved uses. The jury sided with California-based Kaiser Foundation Health Plan Inc. and Kaiser Foundation Hospitals, the first to try a gabapentin case against Pfizer.
Data revealed in a string of U.S. lawsuits indicates the drug was promoted by the drug company as a treatment for pain, migraines and bipolar disorder — even though it wasn't effective in treating these conditions and was actually toxic in certain cases, according to the Therapautics Initiative, an independent drug research group at the University of British Columbia.
The trials forced the company to release all of its studies on the drug, including the ones it kept hidden.
A new analysis of those unpublished trials by the Therapeutics Initiative suggests that gabapentin works for one out of every six or eight people who use it, at best. The review also concluded that one in eight people had an adverse reaction to the drug.
"The much larger majority of people will not get any benefit and many of them will have chronic neurotoxicity or poisoning of the brain," said Dr. Tom Perry of the Therapeutics Initiative.
Dr. Harry Pollett, a pain specialist in North Sydney, N.S., calls gabapentin a so-so drug with potentially serious side-effects for patients. These include drowsiness, balance problems, fogginess and edema, or swelling.
"Weight gain is a very common problem and I see that a lot," Pollett said.
The drugs represent a waste of money for Canada's health-care system, said Perry, who questioned why some doctors continue to encourage people to take the drug even though the patients are not benefiting.
"We have been using probably somewhere in the order of around $300 million a year in Canada recently and this drug has been overused since the late 1990s," Perry said. "So, do the math. It's probably well in excess of a billion dollars."
Pfizer defends its actions and its drug. The company has already been hit with $430 million in penalties and fines for fraudulently promoting gabapentin in the U.S.
SOURCE: CBS NEWS
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