Divalproex Sodium Prescribing Information
General Population:
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months of valproate therapy. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When divalproex sodium delayed-release tablets are used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Divalproex sodium delayed-release tablets are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder
POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, divalproex sodium delayed-release tablets should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with divalproex sodium delayed-release tablets for the development of acute liver injury with regular clinical assessments and serum liver test monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug
Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When divalproex sodium delayed-release tablets are used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease
Divalproex sodium delayed-release tablets are contraindicated in patients:
- with hepatic disease or significant hepatic dysfunction[see Warnings and Precautions (5.1)].
- known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder[see Warnings and Precautions (5.1)].
- with known hypersensitivitytodivalproex sodium, sodium valproate, or valproic acid. Reactions have included multiorgan hypersensitivity, serious dermatologic reactions, and angioedema[see Warnings and Precautions (5.12, 5.13, 5.14)].
- with known urea cycle disorders[see Warnings and Precautions (5.6)].
- being treated for prophylaxis of migraine headaches who are pregnant or in women of childbearing potential who are not using effective contraception[see Warnings and Precautions (5.2, 5.3, 5.4)and Use in Specific Populations (8.1)].
- Hepatic disease or significant hepatic dysfunction
- Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG)
- Suspected POLG-related disorder in children under two years of age
- Known hypersensitivity to divalproex sodium, sodium valproate, or valproic acid
- Urea cycle disorders
- Prophylaxis of migraine headaches: Pregnant women, women of childbearing potential not using effective contraception
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months of valproate therapy. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When divalproex sodium delayed-release tablets are used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Divalproex sodium delayed-release tablets are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder
POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, divalproex sodium delayed-release tablets should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with divalproex sodium delayed-release tablets for the development of acute liver injury with regular clinical assessments and serum liver test monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug
Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores
Valproate is therefore contraindicated for prophylaxis of migraine
Divalproex sodium delayed-release tablets are contraindicated in patients:
- with hepatic disease or significant hepatic dysfunction[see Warnings and Precautions (5.1)].
- known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder[see Warnings and Precautions (5.1)].
- with known hypersensitivitytodivalproex sodium, sodium valproate, or valproic acid. Reactions have included multiorgan hypersensitivity, serious dermatologic reactions, and angioedema[see Warnings and Precautions (5.12, 5.13, 5.14)].
- with known urea cycle disorders[see Warnings and Precautions (5.6)].
- being treated for prophylaxis of migraine headaches who are pregnant or in women of childbearing potential who are not using effective contraception[see Warnings and Precautions (5.2, 5.3, 5.4)and Use in Specific Populations (8.1)].
- Hepatic disease or significant hepatic dysfunction
- Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG)
- Suspected POLG-related disorder in children under two years of age
- Known hypersensitivity to divalproex sodium, sodium valproate, or valproic acid
- Urea cycle disorders
- Prophylaxis of migraine headaches: Pregnant women, women of childbearing potential not using effective contraception
Valproate should not be administered to a woman of childbearing potential
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population
Valproate can cause decreased IQ scores following
Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure
In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits
Because of the risk to the fetus of decreased IQ, neurodevelopmental disorders, and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headaches
Women of childbearing potential should be counseled regularly regarding the relative risks and benefits of valproate use during pregnancy. This is especially important for women planning a pregnancy and for girls at the onset of puberty; alternative therapeutic options should be considered for these patients
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate.
A Medication Guide describing the risks of valproate is available for patients
Advise the patient to read the FDA-approved patient labeling .
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly
Inform pregnant women and women of childbearing potential (including girls beginning the onset of puberty) that use of valproate during pregnancy increases the risk of birth defects, decreased IQ, and neurodevelopmental disorders in children who were exposed
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant.
Encourage women who are taking divalproex sodium delayed-release tablets to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 or visit the website, http://www.aedpregnancyregistry.org/
Counsel patients, their caregivers, and families that AEDs, including divalproex sodium delayed-release tablets, may increase the risk of suicidal thoughts and behavior and to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and to notify the prescriber if any of these symptoms occur
Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.
Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related. Advise patients to report such reactions to a healthcare provider immediately
Advise patients of the early signs and symptoms of severe cutaneous adverse reactions and to report any occurrence immediately to a healthcare provider
Advise patients to discontinue divalproex sodium delayed-release tablets and seek immediate medical care if they develop signs or symptoms of angioedema, such as facial, perioral, or upper airway swelling
Instruct patients to notify their healthcare provider if they notice a medication residue in the stool
East Windsor, NJ 08520
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Revised: 06/2025
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, divalproex sodium delayed-release tablets should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated
Contraindications (
Divalproex sodium delayed-release tablets are contraindicated in patients:
- with hepatic disease or significant hepatic dysfunction[see Warnings and Precautions (5.1)].
- known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder[see Warnings and Precautions (5.1)].
- with known hypersensitivitytodivalproex sodium, sodium valproate, or valproic acid. Reactions have included multiorgan hypersensitivity, serious dermatologic reactions, and angioedema[see Warnings and Precautions (5.12, 5.13, 5.14)].
- with known urea cycle disorders[see Warnings and Precautions (5.6)].
- being treated for prophylaxis of migraine headaches who are pregnant or in women of childbearing potential who are not using effective contraception[see Warnings and Precautions (5.2, 5.3, 5.4)and Use in Specific Populations (8.1)].
- Hepatic disease or significant hepatic dysfunction
- Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG)
- Suspected POLG-related disorder in children under two years of age
- Known hypersensitivity to divalproex sodium, sodium valproate, or valproic acid
- Urea cycle disorders
- Prophylaxis of migraine headaches: Pregnant women, women of childbearing potential not using effective contraception
Warnings and Precautions (
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN), Stevens Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and erythema multiforme (EM) have been reported with valproate treatment. Valproate should be discontinued at the first sign of a rash, unless the rash is clearly not drug related. If
Angioedema has been reported in patients treated with valproate in the postmarketing setting. Valproate should be discontinued immediately if symptoms of angioedema such
Divalproex sodium is an anti-epileptic drug indicated for:
- Treatment of manic episodes associated with bipolar disorder
1.1 ManiaDivalproex sodium delayed-release tablets are a valproate and are indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility.
The efficacy of divalproex sodium delayed-release tablets was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania[see Clinical Studies (14.1)].
The safety and effectiveness of divalproex sodium delayed-release tablets for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use divalproex sodium delayed-release tablets for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. - Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures
1.2 EpilepsyDivalproex sodium delayed-release tablets are indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Divalproex sodium delayed-release tablets are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. - Prophylaxis of migraine headaches
1.3 MigraineDivalproex sodium delayed-release tablets are indicated for prophylaxis of migraine headaches. There is no evidence that divalproex sodium delayed-release tablets are useful in the acute treatment of migraine headaches.
Divalproex sodium delayed-release tablets are intended for oral administration. Divalproex sodium delayed-release tablets should be swallowed whole and should not be crushed or chewed.
Patients should be informed to take divalproex sodium delayed-release tablets every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.
Divalproex sodium delayed-release tablets, USP are supplied as:
- Pregnancy: Divalproex sodium delayed-release tablets can cause congenital malformations including neural tube defects, decreased IQ, and neurodevelopmental disorders (,
5.2 Structural Birth DefectsValproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population
[see Use in Specific Populations (8.1)].,5.3 Decreased IQ Followingin uteroExposure
Valproate can cause decreased IQ scores followingin uteroexposure. Published epidemiological studies have indicated that children exposed to valproatein uterohave lower cognitive test scores than children exposedin uteroto either another antiepileptic drug or to no antiepileptic drugs. The largest of these studies1is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94 to 101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105 to 110]), carbamazepine (105 [95% C.I. 102 to 108]), and phenytoin (108 [95% C.I. 104 to 112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposurein uterocan cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits[seeUse in Specific Populations (8.1)].)8.1 PregnancyPregnancy Exposure RegistryThere is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including divalproex sodium delayed-release tablets, during pregnancy. Encourage women who are taking divalproex sodium delayed-release tablets during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. This must be done by the patient herself.
Risk SummaryFor use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception
[seeContraindications (4)].For use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable
[seeBoxed WarningandWarnings and Precautions (5.2,5.3)]. Women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations). This risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established.
In uteroexposure to valproate may also result in hearing impairment or hearing loss. Valproate polytherapy with other AEDs has been associated with an increased frequency of congenital malformations compared with AED monotherapy. The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies[see.Warnings and Precautions (5.2)and Data (Human)]Epidemiological studies have indicated that children exposed to valproate
in uterohave lower IQ scores and a higher risk of neurodevelopmental disorders compared to children exposed to either another AEDin uteroor to no AEDsin utero[see.Warnings and Precautions (5.3)and Data (Human)]An observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders
[see Data (Human)].In animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses
[see Data (Animal)].There have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy.
Pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death
[see.Warnings and Precautions (5.1,5.8)]Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate.
Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate
[seeWarnings and Precautions (5.2,5.4)].All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal riskTo prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus
[see. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient.Warnings and Precautions (5.4)]Maternal adverse reactionsPregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death
[see. If valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. If abnormal in the mother, then these parameters should also be monitored in the neonate.Warnings and Precautions (5.8)]Patients taking valproate may develop hepatic failure
[see. Fatal cases of hepatic failure in infants exposed to valproateBoxed WarningandWarnings and Precautions (5.1)]in uterohave also been reported following maternal use of valproate during pregnancy.Hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy.
DataHumanNeural tube defects and other structural abnormalities
There is an extensive body of evidence demonstrating that exposure to valproate
in uteroincreases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07% (6 to 7 in 10,000 births) compared to the risk followingin uterovalproate exposure estimated to be approximately 1 to 2% (100 to 200 in 10,000 births).The NAAED Pregnancy Registry has reported a major malformation rate of 9 to 11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. These data show an up to a five-fold increased risk for any major malformation following valproate exposure
in uterocompared to the risk following exposurein uteroto other AEDs taken as monotherapy. The major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems[see.Warnings and Precautions (5.2)]Effect on IQ and neurodevelopmental effects
Published epidemiological studies have indicated that children exposed to valproate
in uterohave lower IQ scores than children exposed to either another AEDin uteroor to no AEDsin utero. The largest of these studies1is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94 to 101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105 to 110]), carbamazepine (105 [95% C.I. 102 to 108]) and phenytoin (108 [95% C.I. 104 to 112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to AEDs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed[see.Warnings and Precautions (5.3)]Although the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure
in uteroand subsequent adverse effects on neurodevelopment, including increases in autism spectrum disorders and attention deficit/hyperactivity disorder (ADHD). An observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders. In this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]: 1.7 to 4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. The absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6% to 7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5% to 1.6%) in children not exposed to valproate products. Another observational study found that children who were exposed to valproatein uterohad an increased risk of ADHD (adjusted HR 1.48; 95% CI, 1.09 to 2.00) compared with the unexposed children. Because these studies were observational in nature, conclusions regarding a causal association betweenin uterovalproate exposure and an increased risk of autism spectrum disorder and ADHD cannot be considered definitive.Other
There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy.
AnimalIn developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following administration of valproate to pregnant animals during organogenesis at clinically relevant doses (calculated on a body surface area [mg/m2] basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate.
- Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (,
5.16 Somnolence in the ElderlyIn a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence
[see Dosage and Administration (2.4)].)8.5 Geriatric UseNo patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence[see Warnings and Precautions (5.16)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence[see Dosage and Administration (2.4)].
There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65.