Consequences of Rampant Off-Label Prescribing of Depakote

Washington, DCThe 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.