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.

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