Depakene (valproic acid (as sodium salt) (valproate sodium))

Dosage of valproate sodium and divalproex sodium is expressed in terms of valproic acid. Dosage must be carefully and slowly adjusted according to individual requirements and response.

Because of a decrease in clearance of free (unbound) valproic acid and the possibility of increased sensitivity to adverse effects (e.g., somnolence) in geriatric patients, the initial dosage should be reduced. Subsequent dosage should be increased more slowly in geriatric patients. In addition, the manufacturer recommends regular monitoring of fluid and nutritional intake, dehydration, somnolence, and other adverse effects in these individuals. Dosage reduction or discontinuance of valproic acid should be considered in geriatric patients with decreased food or fluid intake and in those with excessive somnolence. The ultimate therapeutic dosage in these patients should be determined on the basis of tolerability and clinical response.

Valproate sodium can be administered orally or by IV infusion and valproic acid and divalproex sodium are administered orally. Valproic acid also has been administered rectally+ by enema or in wax-based suppositories.

Patients who are currently receiving or beginning therapy with any anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior. (See Cautions: Nervous System Effects and Cautions: Precautions and Contraindications.)

A medication guide explaining the risks and benefits of valproic acid therapy should be distributed to patients receiving valproic acid, valproate sodium, or divalproex sodium.

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There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

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There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

There is no enhanced messaging for this drug.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

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Use of valproic acid during pregnancy is associated with an increased risk of neural tube defects (NTDs; e.g., spina bifida) and other major congenital malformations (e.g., craniofacial defects, cardiovascular malformations, malformations involving various body systems). In utero exposure to valproic acid also can cause decreased intelligence quotient (IQ) scores and other adverse cognitive effects in children.

Adverse fetal effects similar to those observed in humans have been observed in developmental toxicity studies in animals. Administration of valproic acid to mice, rats, rabbits, and monkeys during the period of organogenesis resulted in an increased incidence of fetal structural malformations (e.g., skeletal, cardiac, urogenital), intrauterine growth retardation, and embryofetal death. Such effects were observed at clinically relevant dosages of valproic acid. In addition, fetal NTDs were observed in mice following valproic acid administration during critical periods of organogenesis; this teratogenic response correlated with maximum maternal drug concentrations. Behavioral abnormalities (e.g., cognitive, locomotor, and social interaction deficits) and brain histopathologic changes also have been observed in mice and rats following prenatal exposure to clinically relevant dosages of valproic acid.

Valproic acid can cause major congenital malformations in humans, particularly NTDs, and this risk appears to be greatest during the first trimester of pregnancy. Recent data indicate that the risk of major congenital malformations is substantially greater with use of valproic acid than with use of other anticonvulsant agents during pregnancy. To monitor maternal-fetal outcomes of pregnant women exposed to anticonvulsant agents, including valproic acid, the North American Antiepileptic Drug (NAAED) pregnancy registry has been established. Data obtained from the NAAED registry indicate that the rate of major malformations in infants exposed in utero to valproic acid as monotherapy is about fourfold higher than the rate of major malformations in infants exposed to monotherapy with another anticonvulsant agent. Among 149 women in the registry who received valproic acid (average daily dosage of 1 g) for epilepsy during the first trimester of pregnancy, 16 infants were born with a birth defect, including NTDs (3 cases), craniofacial defects, cardiovascular defects, and other malformations involving various body systems. The rate of major malformations in infants exposed to valproic acid was 10.7% compared with a rate of 2.9% among infants born to a control group of women in the registry who received another anticonvulsant drug during the first trimester of pregnancy. The strongest association between maternal use of valproic acid and congenital anomalies is with the development of NTDs (e.g., spina bifida). Use of valproic acid during pregnancy is associated with an approximate 1-2% fetal risk of congenital spinal bifida (based on data from the US Centers for Disease Control and Prevention (CDC)); according to data from the CDC's National Birth Defects Prevention Network, the estimated risk of spina bifida in the general population is about 0.06-0.07%. Evidence suggests that prophylactic use of folic acid prior to conception and during pregnancy decreases the incidence of congenital NTDs in the general population, and folic acid supplementation prior to conception and during pregnancy should be routinely recommended in women receiving valproic acid. It is not known whether folic acid supplementation specifically reduces the risk of NTDs or decreased IQ in the offspring of women receiving valproic acid therapy.

In utero exposure to valproic acid also appears to be associated with an increased risk of adverse cognitive effects in children. Several epidemiologic studies have shown that children born to women who received valproic acid during pregnancy score lower on IQ tests and other cognitive function tests measuring a variety of mental and developmental abilities than those exposed in utero to other anticonvulsant agents or to no anticonvulsant therapy. In one large, prospective, observational cohort study (the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study), children who had been exposed to valproic acid in utero had significantly lower IQ scores at 6 years of age than those exposed in utero to lamotrigine, phenytoin, or carbamazepine monotherapy. After adjustment for potentially confounding factors, IQ scores were on average 8-11 points lower in valproic acid-exposed children compared with those exposed to the other anticonvulsant drugs. These findings of reduced IQ were consistent with those reported in 2 interim analyses that were conducted when the children were 2-3 and 4.5 years of age, although overall IQ scores tended to improve with age. Fetal exposure to valproic acid also was associated with impairments in a range of other cognitive domains (e.g., memory, verbal and nonverbal abilities, executive functions, cognitive fluency and originality); in general, the effects of the drug were dose dependent, with higher dosages associated with worse cognitive outcomes. Other observational studies also have demonstrated poorer cognitive outcomes, including delayed mental development, increased special education needs, and reduced verbal IQ, in cohorts of children exposed in utero to valproic acid compared with other anticonvulsant agents. Despite the methodologic limitations of these studies (e.g., lack of randomization, small sample size), the weight of available evidence currently supports a correlation between prenatal valproic acid exposure and an increased risk of cognitive deficits, including decreased IQ, in children. The long-term effects of prenatal valproic acid exposure on cognitive development have not been established. It is also not known whether these effects occur when fetal exposure is limited with respect to duration or timing (e.g., to the first trimester) during pregnancy. Therefore, the risk for development of adverse cognitive effects in valproic acid-exposed children should be considered at any time during pregnancy. In the NEAD study, a positive association was found between periconceptional use of folic acid and IQ scores; however, this finding should be interpreted with caution because the study was not specifically designed to evaluate this outcome. Folic acid supplementation prior to conception and during pregnancy should be routinely recommended in all women of childbearing age receiving valproic acid to decrease the risk of birth defects.

There also is a possible association between in utero valproic acid exposure and developmental delay, autism, or autism spectrum disorders. Results of a population-based cohort study using national register data from Denmark found that maternal use of valproic acid during pregnancy was associated with an increased risk of autism spectrum disorders and childhood autism in the offspring. The study identified a cohort of children (total of 655,615) born during a 10-year period and followed these children from birth until death, emigration, diagnosis of autism spectrum disorder or childhood autism, or study end. Among 508 children who were identified as having been exposed to valproic acid in utero, the absolute risk of autism spectrum disorder was 4.42% (adjusted hazard ratio of 2.9) and the absolute risk of childhood autism was 2.5% (adjusted hazard ratio of 5.2); the estimated absolute risk of these disorders in the entire population of children studied was 1.53 and 0.48%, respectively, after 14 years of follow-up.

Valproic acid is contraindicated in pregnant women for the prevention of migraine headaches. The drug should not be used in pregnant women with epilepsy or bipolar disorder unless other treatments have failed to provide adequate symptom relief or are otherwise unacceptable; in these cases, the benefits of valproic acid may continue to outweigh its risks. It should be kept in mind that untreated or inadequately treated epilepsy or bipolar disorder during pregnancy increases the risk of complications in both the pregnant woman and her developing fetus.

Because of the risk of major congenital malformations and other adverse pregnancy outcomes (e.g., decreased IQ in offspring) which may occur very early in pregnancy, use of valproic acid should be avoided whenever possible in women of childbearing potential. Alternative therapies to valproic acid should be considered, especially if the drug is being used for the treatment of migraines or other conditions not usually considered life-threatening, in women of childbearing potential. If valproic acid is necessary in a woman of childbearing potential, some experts suggest that the lowest possible dosage be employed. Effective contraception should be used in such women during valproic acid therapy. If pregnancy occurs during therapy, the clinician should be notified immediately; valproic acid should not be discontinued abruptly in a pregnant woman with epilepsy because of the risk of precipitating seizures. In individual cases when the severity and frequency of the seizure disorder are such that discontinuance of therapy does not pose a serious threat to the patient, discontinuance of the drug may be considered prior to and during pregnancy; however, even minor seizures can pose some hazard to the developing embryo or fetus.

In women who are contemplating pregnancy, alternative therapies to valproic acid should be considered; clinicians should review and revise the treatment plan with the patient well before conception. Women who become pregnant while receiving valproic acid should be encouraged to enroll in the NAAED pregnancy registry by calling 888-233-2334; information on the NAAED registry also is available on the website http://www.aedpregnancyregistry.org. Tests to detect neural tube and other malformations using current accepted procedures should be considered a part of routine prenatal care and be offered to all women who become pregnant while receiving valproic acid.

Patients receiving valproic acid may develop clotting abnormalities. A pregnant patient taking multiple anticonvulsant agents, including valproic acid, developed hypofibrinogenemia; the patient then gave birth to an infant with afibrinogenemia, who subsequently died of hemorrhage. If valproic acid is to be used during pregnancy, clotting parameters should be monitored closely.

Cerebral atrophy has been reported in children following prenatal exposure to valproic acid. In addition, fatal cases of hepatic failure in infants exposed to valproic acid in utero have been reported. (See Cautions: Hepatic Effects and see also Cautions: Precautions and Contraindications.)

Valproic acid is distributed into milk; caution is advised when administering the drug to nursing women.

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