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The Drug

Synthesis of valproate first occurred in the late 1800s, and was subsequently used as a ‘metabolically inert’ vehicle for drug delivery. Nearly 80 years later, French scientist Pierre Eymard serendipitously discovered the anticonvulsant potential of the drug during a routine screening of potential antiepileptic drugs (AEDs) using Valproate as a vehicle. Shortly thereafter, Abbot Labs received FDA approval in 1978 to market the drug for the treatment of epilepsy under the trade name Depakene.

Epilepsy can very generally be described as a chronic disorder of brain dysfunction due to excessive neuronal discharge. Put another way, brain cells communicate with neighboring neurons in part by generating electrical currents called action potentials. When an action potential is emitted, the neuron fires an electrical charge which ultimately causes the release of neurotransmitters which then travel to neighboring neurons. These neurotransmitters comprise the means by which neurons communicate and influence the activity and behavior of neighboring neurons. In epileptics, this method of cellular communication becomes dysfunctional, and neurons begin firing uncontrollably and with greater frequency, resulting in impaired motor function and consciousness. Valproate products prevent the initiation of such dysfunctional communications between neurons primarily through two mechanisms. First, valproate inhibits certain neuronal channels (called voltage gated calcium and sodium channels) necessary for the neuron to generate an action potential, in turn reducing the ability of the cell to fire. In addition, the drug blocks the degradation of the neurotransmitter GABA, an inhibitory chemical messenger found in the brain which also decreases the ability of the neuron to initiate action potentials. For reference, GABA is the main target of many anti-anxiety drugs and sleep medications as they dampen neuronal activity. Together, these mechanisms of action make it more difficult for neurons to fire, resulting in the reduced capacity to initiate and sustain an epileptic episode.

Today, valproate and its related analogues are marketed as Depakene, Depacon, Divalproex sodium (known also as Depakote, Depakote CP, and Depakote ER), and Stavzor. It remains one of the most prescribed AEDs on the market, and has received FDA approval for the treatment of epilepsy, manic episodes associated with bipolar disorder, and as a prophylactic treatment for migraines. Off-label uses, or uses that have not received FDA approval, include borderline personality disorder, Alzheimer’s related disorders, post-traumatic stress disorder, and others. Currently, the Department of Justice is investigating Abbot Labs for alleged illegal marketing and promotion of Depakote for off-label uses.

The Controvery

The teratogenic potential of valproate has been documented since 1980. In 1982, researchers found a 20-fold risk of spina bifida in children exposed to valproate in utero, and in 1984, the medical community recognized a constellation of minor and major malformations called Fetal Valproate Syndrome. Despite these advances in understanding, only recently has the extraordinary range and danger of the drug become documented and appreciated.

The risk of birth defects following in utero exposure to valproate is extraordinarily high and produces a wide-range of birth defects. For example, in a 2005 study published in Neurology, researchers analyzed outcomes in 1,956 women taking AEDs during the first trimester of pregnancy. Compared to the average incidence of birth defects in the general unexposed population (a rate of 1.62%), valproate produced a 7-fold greater risk for major malformations. The authors concluded that, in addition to previously reported birth defects, valproate produced an unacceptable risk of developing additional, previously unknown defects including pulmonary atresia, craniosynostosis, and metopic synostosis. The authors also reported that the risk of neural tube defects (e.g. spina bifida) following first trimester valproate exposure is 1 in 20, whereas in the general population the risk remains at 1 in 1500.

Similar results were observed in a 2006 study in which researchers published one of the more important studies in the field looking at the incidence of malformations in the US and UK following first trimester exposure to antiepileptic drugs. Their results exhibited an extraordinary rate of malformations following exposure to valproate, finding that 20.29% of births resulted in serious adverse outcomes. Furthermore, the risk presented by valproate was twice that of the second most dangerous AED studied, phenytoin, which produced a risk percentage of 10.71%. The effects were dose related, with valproate doses above the median increasing the risk of adverse outcomes to 24.2%.

In response to these studies and others, in 2009 the FDA issued a statement for patients and healthcare professionals warning that valproate products increase the risk of neural tube defects, craniofacial defects such as cleft palate and cleft lip, and cardiovascular malformations. This warning concluded with an assertion by the FDA that they were actively involved in working with manufacturers to update labeling information.

Fetal exposure to valproate also impairs the cognitive development of children, resulting in decreased IQ. This conclusion was reached in a 2009 study published in the New England Journal of Medicine. In the study, researchers in both the US and UK pooled results from mothers and their children exposed to AEDs during pregnancy, and determined the average child’s IQ by drug. Results exhibited that on average, children exposed to valproate had a significantly lower average IQ than children exposed to alternative AEDs such as lamotrigine, carbamazepine, and phenytoin. The study confirmed results seen in a number of previous studies from throughout the world, in both children and in animals. In response to these data and others, the FDA issued a bulletin in June of 2011 warning patients and healthcare professionals that first trimester exposure to valproate products may impair cognitive development. Importantly, the FDA also warned that the long-term effects of the drug on cognitive development remain unknown.

As it currently stands, the list of potential defects following valproate exposure is immense. Some of the more predominant defects include:

  • Premature birth
  • Low birth weight
  • Newborn withdrawal
  • Disrupted cognitive development
  • Craniofacial defects such as cleft lip and cleft palate
  • Neural tube defects such as spina bifida.
  • Congenital heart defects such as ventral septal defects
  • Genital abnormalities such as hypospadias
  • Limb defects such as extra or missing digits
  • Malformed limbs and skeletal defects such as radial ray defects and phalangeal hypoplasia (both involve defects in finger bones)
  • Craniosynostosis (abnormal formation of the skull)
  • Fetal Valproate Syndrome, which is associated with
    • Musculoskeletal abnormalities
    • Minor skin defects
    • Cardiovascular abnormalities
    • Neural tube defects
    • Anomalies of the eye, brain, kidney, and hearing.
    • Growth retardation
    • Infant death
    • Mental retardation

Others, which are not as well characterized but nonetheless have been reported in the literature include:

  • Inguinal and umbilical hernias
  • Supernumerary nipple (an accessory nipple)
  • Postaxial polydactyly (fifth digit duplication in the hands or feet)
  • Bifid ribs
  • Congenital heart disease
  • Septal defects and valvular problems
    • Aortic valve stenosis
    • Interrupted aortic arch
    • Secundum atrial septal defects
    • Pulmonary atresia without ventral septal defects
    • Perimembranous ventral septal defects
    • Hypoplastic left heart syndrome
    • Coarctation of the aorta
    • Atrial septal defects
  • Brachycephaly (flat head syndrome)
  • Hydronephrosis (obstruction of the free flow of urine from the kidney)
  • Undescended testes
  • Dysplastic ribs (abnormal growth/development of the ribs)
  • Pulmonary stenosis (obstructed blood outflow from the heart)
  • Pulmonary atresia (obstructed blood flow from the heart to the lungs)
  • Metopic synostosis (abnormal head shape and impaired brain growth)
  • Tetralogy of fallot (heart defects which result in low oxygenation of the blood)
  • Microcephaly (abnormally small head)
  • Failure to thrive in newborn infants
  • Hypotonia (decreased muscle tone and weakness)
  • Bilateral multicystic dysplastic kidneys
  • Lamboid suture synostosis (deformity of the skull

Contact Us

If you or a loved one have taken Depakote, Depakene, Depakon, or Stayzor and suffered from any side effects please contact Kondos & Kondos today. Attorneys are available by phone, e-mail, or by clicking here.