The Bitter Pill

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Off-Label Depakote Sales Stronger Than Ever

Evelyn Pringle February 11, 2007

The epilepsy drug, Depakote, earned Abbott Laboratories $384 million in the 4th quarter of 2006, and overall sales rose 18.5% to $1.2 billion last year.

The rising sales are a result of Depakote (valproate) being increasingly prescribed for conditions other than epilepsy like mood disorders, manic depression and migraines. Doctors are also prescribing Depakote as a mood stabilizer in off-label combinations with other drugs for uses that have never been FDA approved or tested for safety and efficacy.

Although in the US, drug companies are prohibited by law from promoting the sale of a drug for an off-label use, once a medication is FDA approved for once indication, doctors are free to prescribe it for other conditions if they believe it will be beneficial to a patient.

However, in recent years the rate of off-label prescribing has become epidemic and many drug companies have paid huge fines after being caught promoting drugs for unapproved uses and many more are currently under investigation for illegal marketing schemes.

In 2001, a study by the Agency for Healthcare Research and Quality (AHRQ) found that about 21% of prescriptions written in the US are for conditions not indicated on the label and cardiac medications and anticonvulsants were the most commonly prescribed for unapproved uses. Most off-label use, the study pointed out, occurs without scientific support.

Depakote is one of the drugs prescribed most often off-label, and experts say its not unusual to find patients on Depakote along with 3 or 4 other medications all at once.

On October 13, 2006, the FDA revised the labeling for Depakote to warn of adverse events associated with use of the drug during pregnancy and said that Depakote should only be considered for women of childbearing years if it was essential for the treatment of their condition and the risks and benefits were fully discussed with the patient.

According to the North American Antiepileptic Drug Pregnancy Registry, Depakote use during the first trimester of pregnancy is linked to a 4-fold increased risk of congenital malformations when compared with other antiepileptic drugs (AEDs). The rate malformations with infants exposed to Depakote was 10.7%, or 16 cases in 149 births.

The Registry is set up to determine the safety of anticonvulsants to help gauge the frequency of malformations, such as heart defects, spina bifida and cleft lip. Only major malformations are included in the Registry, defined as a structural abnormality of the infant with surgical, medical, or cosmetic importance.

The CDC reports that the risk of spina bifida among infants born to mothers receiving Depakote during the first trimester is estimated to be 1% to 2%, compared to 0.14% to 0.2% in the general population according to the American College of Obstetricians and Gynecologists.

Although Depakote is most strongly associated with neural tube defects, the FDA notes that other anomalies have also been reported, such as craniofacial defects, cardiovascular malformations, and anomalies involving various body systems with some fatal.

Drugs that cause malformations are known as teratogens. A teratogen can disturb the development of the fetus, halt the pregnancy, or permit the pregnancy to proceed but produce a congenital malformation or birth defect.

Due to the rate of off-label prescribing, pregnant women may be receiving Depakote for other indications and the FDA warns that the increased risk associated with Depakote in pregnant women treated for epilepsy likely reflects an increased risk in treatment for other conditions as well, such as migraines or bipolar disorder.

Depakote has now been moved into “Category C” for pregnant women, which means animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women, or no animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women.

In the case of Depakote, numerous animal studies have established drug-induced teratogenicity. Increased malformations, as well as growth retardation and death, have been found in rats, mice, rabbits, and monkeys following prenatal exposure to the drug, according to the FDA’s information listed on Depakote.

Malformations of the skeletal system are the most common structural abnormalities observed in animals, but neural tube closure defects have been seen in mice exposed to plasma Depakote concentrations exceeding 2.3 times the upper limit of the human therapeutic range during periods of embryonic development.

An oral dose equal to about 50% of the maximum human daily dose administered to pregnant rats produced skeletal, cardiac, and urogenital malformations and growth retardation in the offspring. Behavioral deficits have also been reported in the offspring of rats given Depakote throughout most of the pregnancy.

An oral dose of approximately 2 times the maximum human daily dose produced skeletal and visceral malformations in rabbits exposed during organogenesis.

Skeletal malformations, growth retardation, and death have been observed in rhesus monkeys following administration of an oral dose equal to the maximum human daily dose during organogenesis.

The initial report from on-going human study titled, “Neurodevelopmental Effects of Antiepileptic Drugs,” in the August 8, 2006, journal, Neurology, found that major congenital abnormalities were more common in infants exposed to Depakote than those exposed to one of 3 other AEDs.

A team of researchers led by Dr Kimford Meador, of the University of Florida, are conducting a study on pregnant women with treated for epilepsy from October 1999 to February 2004, receiving either Depakote, Dilantin, Lamictal, or Tegretol.

The initial report, focuses on the rate of serious adverse events including fetal death or major congenital malformations defined as structural abnormalities with surgical, medical, or cosmetic importance identified during pregnancy, at birth, between birth and 1 year, or at 73 weeks.

The researchers identified 6 fetal deaths and 22 malformations that included malformed hearts and genitals, cleft palate, and artery deformities, with 20.3% found in women taking Depakote.

Based on these initial findings, the researchers advised that Depakote should not be used as the first choice for women of childbearing potential, and if used, its dose should be limited when possible.

In an interview with Shawna Cutting, posted on Epilepsy.com, Dr Meador explained how he became interested in doing the study. “Over the years,” he said, “I began to think that these effects might be dramatic in children while their brains are developing, because they could add up over many years.”

“That made me think that the effect might be even greater in a fetus because brain development there is so rapid,” he said.

“The process of physical growth and the attainment of intelligence and problem-solving ability that begins in infancy; any interruption of this process by a disease or disorder is called developmental delay,” Dr Meador explained.

He said studies of animals clearly showed that some antiepileptic drugs could affect behavior of the offspring.

His on-going study will track children until they are 2 or 3, but says children need to be followed until they are at least 6. “This age is so important,” Dr Meador said during the interview, “because this is when measures such as IQ begin to match up with adult measures.”

“If you measure a child’s IQ at 3 years of age,” he explained, “it may not predict the child’s development.”

“But a measurement at 6 years of age,” he said, “statistically will predict what will happen when this kid is an adult.”

He also noted that this is an important point because children begin school at that age and whatever is going on will effect their learning and said, a “disturbing report” on a study from England suggested that Depakote was producing worse effects.

Filed under: 2007, Abbott, anticonvulsants, Birth Defects, Depakote, FDA, prices, suicide

Consequences of Rampant Off-Label Prescribing of Depakote

Evelyn Pringle February 7, 2007

The antiepileptic drug, Depakote, is one of the most heavily prescribed medications for off-label use. The Epilepsy Foundation reports that there are an estimated 1 million women in the US with epilepsy, but the number of women being treated with antiepileptics is two to three times higher than the number of women with the disorder.

Experts say the evidence of harm caused by the massive off-label prescribing of Depakote (valproate), marketed by Abbott Laboratories, is just beginning to surface.

According to Harrisburg, Pennsylvania psychiatrist, Dr Stefan Kruszewski, a recognized expert on psychotropic drugs, “we can anticipate a continuing series of tragic outcomes from the massive overuse of Depakote, secondary not only to birth defects and death, but also due to anemias, hepatic disease, obesity, diabetes type II, pancreatitis and other serious systemic and neurological dysfunctions.”

Drugs are FDA-approved for specific indications, but they can be prescribed off-label for other conditions if a doctor deems it appropriate. Although drug makers are prohibited by law from promoting their drugs for off-label uses, its a well known fact that they do it all the time.

“Off-label” includes prescribing drugs for uses that are not listed in the FDA-approved labeling; increasing the recommended dose or duration of treatment; combining one drug with other drugs; or prescribing a drug for patient populations, such as children or the elderly, for whom it was not approved.

The truth is, millions of patients are receiving powerful psychotropic drugs like Depakote that have not been approved for treating their specific illness because drug makers are using every trick in the book to boost profits by getting doctors to prescribe their drugs off-label, and as a result patients are serving as guinea pigs.

Off-label use, by definition, means the drug lacks sufficient clinical evidence to demonstrate safety and effectiveness, and therefore, prescribing a drug for unapproved uses exposes patients to the unknown risks of a medication that has no proven benefit.

Doctors are prescribing Depakote together with other drugs in combinations that have never been tested on any patient population. Experts say its not uncommon to see patients, including very young children, taking Depakote along with 3 or 4 other psychiatric drugs all at the same time.

And, contrary to what the drug makers say publicly, they know exactly how many prescriptions are written off-label for each and every drug they sell because they purchase records that show the prescribing habits for all doctors in the US, from data mining firms so that sales representatives can keep track of the prescribing habits of their doctor-customers.

On August 6, 2006, former sales rep, Kathleen Slattery-Moschkau, told the San Francisco Chronicle, that she received reports on all the doctors in her sales territory broken down by drug category which she said helped her determine which doctors “were worthy of spending my monthly budgets on for lunches, dinners, days at the spa, etc.”

Ms Slattery-Moschkau claims she could immediately measure the success of a perk simply by looking at the prescribing records. “If I brought in lunch one week,” she stated, “I could see the following week if that lunch had an impact.”

For good reason, drug companies are willing to pay top dollar for these records. According to the Chronicle, in 2005, the data main data mining firm, IMS Health, had revenues of $847 million from its “Sales Force Effectiveness Offerings.”

Over the past few years, there have been many reports in the media about the over-prescribing of psychiatric drugs, but not much has been written about the off-label sale of Depakote. “In recent years,” Dr Kruszewski says, “Depakote may have escaped some of the media scrutiny of other antiepileptic drugs, like Neurontin, Topamax and Gabitril.”

“As a clinical investigative psychiatrist,” he states, “my concern is that Depakote is widely used on and off-label for so many neuropsychiatric conditions.”

“It has widespread use,” he notes, “for mood disorders, mood swings, anxiety, drug withdrawal states, agitation, aggression, panic disorders and psychosis.”

“It is not a benign drug,” he warns.

Dr Kruszewski says a number of recent reports by scientific experts, including one on birth defects discussed in Neurology Journal Watch, are worrisome. “Depakote, in a dose-dependent fashion,” he states, “is associated with fetal abnormalities and fetal death.”

“Depakote appears to increase the risk of spina bifida and significantly increases the risk of other neural tube defects,” he notes.

“Fetal serum concentrations,” he explains, “are typically 1.4 times greater than those of the mother and incur a longer half-life.”

“The evidence is uncertain,” he says, “regarding what neurological or other effects are sustained by breast-fed infants of mothers who take Depakote.”

One of the recent studies cited by Dr Kruszewski is the Neurodevelopmental Effects of Antiepileptic Drugs, published in the August 8, 2006, issue of Neurology, which reported that major congenital abnormalities are more common in infants whose mothers received Depakote during pregnancy than infants exposed to other antiepileptic drugs.

To determine whether fetal outcomes varied as a result of exposure to four different drugs, a group of researchers led by Dr Kimford Meador, of the University of Florida in Gainesville, conducted a study on pregnant women with epilepsy from October 1999 to February 2004, enrolled in 25 epilepsy centers in the US and UK. A total of 333 mothers were followed, each receiving either Depakote, Lamictal, Dilantin, or Tegretol.

The researcher’s initial report in this ongoing study, focused on the incidence of serious adverse events including major congenital malformations or fetal death, with major malformations defined as structural abnormalities with surgical, medical, or cosmetic importance detected during pregnancy, at birth, from birth to 1 year, or at 73 weeks.

All total, the researchers found there were 6 fetal deaths and 22 malformations, with 20.3% being attributed to Depakote. The birth defects noted included malformed hearts and genitals, cleft palate, and artery deformities.

The risks of birth defects with Depakote have actually been known for quite some time. Back on April 29, 2004, WebMD warned that infants born to women taking Depakote were more likely to have birth defects, and said that whenever possible women should avoid taking the drug not only during pregnancy, but also during childbearing years.

WebMD discussed a study presented at the annual meeting of the American Academy of Neurology, that found death of the fetus, birth defects, and developmental delays, such as walking and speech delays, occurred in 28% of children exposed to Depakote compared with just 2% of infants exposed to Lamictal.

The research team even presented the data from its 5-year study a year earlier than planned because the findings were so alarming.

Lead researcher, Dr Page Pennell, of Atlanta’s Emory University School of Medicine, told WebMD, “The evidence against the use of [Depakote] by women during pregnancy is mounting, but the message has not gotten out.”

She pointed out that “the drug is being increasingly prescribed for other conditions like migraines, bipolar disorder, and mood disorders.”

Depakote is but one of many psychiatric drugs that are not recommended for pregnant women but were recently found to be prescribed off-label to pregnant teens in foster care in Texas.

In fact, Depakote was one of the drugs most prescribed off-label for Texas foster children in general, and the most prescribed anticonvulsant. In fiscal 2004, there were 18,705 prescriptions written for Depakote and its generic equivalent, totaling $1,652,776, making it the third most prescribed psychotropic drug to foster children, according to Health and Human Services Commission and Texas Comptroller of Public Accounts, in a June 2006, Special Report, Foster Children: Texas Health Care Claims Study.

A review of Medicaid records during the investigation that resulted in the report, revealed several cases in which pregnant girls received “category D” medications such as Depakote. The FDA places drugs in the “D” category only when post-marketing data has shown they pose a clear risk to the fetus.

As a whole, anticonvulsants were the second most expensive psychiatric drug category for foster children that year supposedly prescribed as “mood stabilizers,” at a cost of $4.8 million. According to the Zito/Safer External Review, anticonvulsant use for mood stabilization is a poorly evidenced area of psychopharmacology for children and adolescents. But nonetheless, the Texas Medicaid program was charged an average of $111 per prescription for their off-label use.

In addition to the increased risk of birth defects in infants born to pregnant girls on Depakote, the National Institute of Mental Health reports other serious side effects associated with use of the drug by teenage girls:

“According to studies conducted in Finland in patients with epilepsy, valproate may increase testosterone levels in teenage girls and produce polycystic ovary syndrome in women who began taking the medication before age 20. Increased testosterone can lead to polycystic ovary syndrome with irregular or absent menses, obesity, and abnormal growth of hair. Therefore, young female patients taking valproate should be monitored carefully by a physician.”

Dr Kruszewski says doctors and women of childbearing age both need to be aware of the risks to the fetus from Depakote, if a seizure medication is absolutely necessary during pregnancy. Because women often do not know they are pregnant in the initial 4 to 8 weeks of the first trimester, he recommends that women and their doctors plan ahead to use a different drug before a pregnancy begins.

Filed under: 2007, Abbott, anticonvulsants, Birth Defects, Depakote, suicide

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