Depakote

Depakote is the brand name for divalproex sodium (also known as valproic acid), an anti-seizure drug used to treat epilepsy, some mood disorders (like bipolar disorder), and migraine headaches.

It's thought to work by increasing the amount (or mimicking the action) of a neurotransmitter, GABA, in the brain, but the exact mechanism is unknown.

Increasing levels of GABA may help prevent brain signals that lead to seizures.

Restoring the natural balance of chemicals in the brain is also believed to help lessen the severe mood swings associated with bipolar disorder (formerly known as manic depression).

The Food and Drug Administration (FDA) approved Depakote for epilepsy treatment in 1983.

It was approved to treat bipolar disorder in 1995, and in 1996 it was approved for use as a migraine prevention medication. Abbot Laboratories manufactures Depakote.

In 2012, Abbot Laboratories pleaded guilty to federal charges for marketing Depakote as a drug to control agitation and aggression in elderly nursing home patients.

They also marketed Depakote as a schizophrenia medication, even though their own studies showed no benefit.

Neither of these uses had FDA approval. Abbot agreed to pay $1.6 billion to settle the case.

Depakote Warnings

The FDA requires Depakote to carry a black-box warning because it can cause serious liver damage that could be fatal, especially in children younger than 2.

The risk of this happening is higher in the first six months of taking the drug. In some cases liver damage continued even after patients stopped taking Depakote.

There is an additional black-box warning linking Depakote to cases of life-threatening pancreatitis.

In some cases, patients who developed pancreatitis rapidly went from initial symptoms to death, so getting medical treatment quickly is essential.

If you develop abdominal pain, nausea, vomiting, and a stomach that is tender to the touch, call 911 immediately.

Pancreatitis was reported in people who took this drug for a short time as well as in those who took it for years.

You should not take Depakote if you have a history of liver disease, a urea cycle disorder, or a genetic disorder such as Alpers' disease (a progressive degenerative disease of the central nervous system that occurs mostly in infants and children), or Alpers-Huttenlocher syndrome (the formal name for Alper's Disease).

Depakote and Pregnancy

The FDA warns Depakote can harm an unborn baby. Women who take this medication while pregnant could give birth to a child with serious birth defects.

The most common are those that affect the brain and spinal cord, particularly spina bifida or neural tube defects. These defects occur in one or two babies out of 100 that are exposed to Depakote before birth.

Unfortunately, these defects can develop in the very first month of pregnancy, before you even know you are pregnant.

Studies also show if you take Depakote during pregnancy, your child is at risk for having a lower IQ.

The FDA warns that women who take this drug should use effective birth control to prevent pregnancy.

Depakote passes into breast milk. There have not been reports of harm to breastfeeding infants, but talk to your doctor about any risks to your child before you begin breastfeeding.

Depakote is a prescription medication used to treat seizures and manic episodes in people with bipolar disorder and to prevent migraines. 

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Depakote is part of the drug class:

• Fatty acid derivatives

Serious side effects have been reported with Depakote. See “Depakote Precautions” section.

Common side effects of Depakote include:

• upset stomach and nausea
• blurred vision
• constipation
• depression
• diarrhea
• dizziness
• drowsiness
• headache, increased appetite
• insomnia
• nervousness
• rash
• tremor
• vomiting
• weight gain or weight loss
• changes in appetite
• back pain
• changes in mood or mood swings
• abnormal thinking
• ringing in the ears
• hair loss

This is not a complete list of Depakote side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

The following serious adverse reactions are described below and elsewhere in the labeling:

• Hepatic failure [see Warnings and Precautions (5.1)]
• Birth defects [see Warnings and Precautions (5.2)]
• Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)]
• Pancreatitis [see Warnings and Precautions (5.5)]
• Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.9, 5.10)]
• Suicidal behavior and ideation [see Warnings and Precautions (5.7)]
• Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.8)]
• Hypothermia [see Warnings and Precautions (5.11)]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see Warnings and Precautions (5.12)]
• Somnolence in the elderly [see Warnings and Precautions (5.14)]

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Mania

The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively.

Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo.

The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials:

Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity.

Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation.

Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess.

Hemic and Lymphatic System: Ecchymosis.

Metabolic and Nutritional Disorders: Edema, peripheral edema.

Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching.

Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo.

Respiratory System: Dyspnea, rhinitis.

Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea.

Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus.

Urogenital System: Dysmenorrhea, dysuria, urinary incontinence.

Epilepsy

Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote-treated patients (6%), compared to 1% of placebo-treated patients.

Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.

Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs.

The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures:

Body as a Whole: Back pain, chest pain, malaise.

Cardiovascular System: Tachycardia, hypertension, palpitation.

Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.

Hemic and Lymphatic System: Petechia.

Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.

Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.

Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder.

Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.

Skin and Appendages: Rash, pruritus, dry skin.

Special Senses: Taste perversion, abnormal vision, deafness, otitis media.

Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.

Migraine

Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%).

Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients.

The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials:

Body as a Whole: Chest pain, chills, face edema, fever and malaise.

Cardiovascular System: Vasodilatation.

Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis.

Hemic and Lymphatic System: Ecchymosis.

Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase.

Musculoskeletal System: Leg cramps and myalgia.

Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo.

Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis.

Skin and Appendages: Pruritus and rash.

Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus.

Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of Depakote. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatologic: Hair texture changes, hair color changes, photosensitivity, erythema multiforme, toxic epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome.

Psychiatric: Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance in attention, learning disorder, and behavioral deterioration.

Neurologic: Paradoxical convulsion

There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate discontinuation.

There have been reports of acute or subacute encephalopathy in the absence of elevated ammonia levels, elevated valproate levels, or neuroimaging changes. The encephalopathy reversed partially or fully after valproate discontinuation.

Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness.

Hematologic: Relative lymphocytosis, macrocytosis, leukopenia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.

Endocrine: Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion.

There have been rare reports of Fanconi's syndrome occurring chiefly in children.

Metabolism and nutrition: Weight gain.

Reproductive: Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology.

Genitourinary: Enuresis and urinary tract infection.

Special Senses: Hearing loss.

Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis.

Depakote tablets (divalproex sodium delayed-release tablets) are supplied as:

125 mg salmon pink-colored tablets:

Bottles of 100………………………………………..(NDC 0074-6212-13)

Unit Dose Packages of 100.................………………(NDC 0074-6212-11)

250 mg peach-colored tablets:

Bottles of 100……………………………………….(NDC 0074-6214-13)

Bottles of 500……………………………………….(NDC 0074-6214-53)

Unit Dose Packages of 100................………………(NDC 0074-6214-11)

500 mg lavender-colored tablets:

Bottles of 100……………………………………….(NDC 0074-6215-13)

Bottles of 500……………………………………….(NDC 0074-6215-53)

Unit Dose Packages of 100................……………...(NDC 0074-6215-11)

Recommended Storage: Store tablets below 86°F (30°C).

You should not use Depakote if you are allergic to divalproex sodium, or if you have:

• liver disease;

• a urea cycle disorder; or

• a genetic mitochondrial (MYE-toe-KON-dree-al) disorder such as Alpers' disease or Alpers-Huttenlocher syndrome, especially in a child younger than 2 years old.

Depakote can cause liver failure that may be fatal, especially in children under age 2 and in people with liver problems caused by a genetic mitochondrial disorder.

To make sure this medicine is safe for you, tell your doctor if you have:

• liver problems caused by a genetic mitochondrial disorder;

• a history of depression, mental illness, or suicidal thoughts or actions;

• a family history of a urea cycle disorder or infant deaths with unknown cause; or

• HIV or CMV (cytomegalovirus) infection.

Some young people have thoughts about suicide when first taking Depakote. Your doctor will need to check your progress at regular visits while you are using this medicine. Your family or other caregivers should also be alert to changes in your mood or symptoms.

Do not use Depakote to prevent migraine headaches if you are pregnant.

If you take Depakote for seizures or manic episodes: This medicine can harm an unborn baby or cause birth defects, and may affect cognitive ability (reasoning, intelligence, problem-solving) later in the child's life. However, having a seizure during pregnancy could harm both the mother and the baby. Do not start or stop taking the medicine during pregnancy without your doctor's advice.

Use effective birth control while using Depakote, and tell your doctor right away if you become pregnant.

Tell your doctor if you start or stop using hormonal contraception that contains estrogen (birth control pills, injections, implants, skin patches, and vaginal rings). Estrogen can interact with divalproex sodium and make it less effective in preventing seizures.

Seizure control is very important during pregnancy. The benefit of preventing seizures may outweigh any risks posed by taking Depakote. There may be other seizure medications that can be more safely used during pregnancy. Follow your doctor's instructions about taking this medicine while you are pregnant.

Divalproex sodium can pass into breast milk and may harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

• Time to peak effect depends on the formulation used; tablets take 4 hours to reach a peak, Depakote sprinkles just over three. Food can delay absorption (has a more significant effect on the tablets compared with sprinkles).
• May take several weeks before an effect on mood or seizure frequency is seen.

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Because of the low levels of this drug in breastmilk and infant serum, no adverse reactions during breastfeeding have been reported. Theoretically, breastfed infants are at risk for drug-induced hepatotoxicity, so infants should be monitored for jaundice and other signs of liver damage.

UK: A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. US: Caution should be exercised when valproate is administered to a nursing woman. Excreted into human milk: Yes (at a concentration ranging from 1% to 10% of maternal serum levels)

Summary of Use during Lactation

Divalproex results in valproic acid in the maternal bloodstream. Because of the low levels of valproic acid in breastmilk and infant serum, no unquestionable adverse reactions to valproic acid during breastfeeding have been reported. Theoretically, breastfed infants are at risk for valproic acid-induced hepatotoxicity, so infants should be monitored for jaundice and other signs of liver damage during maternal therapy. A questionable case of thrombocytopenia has been reported, so monitor the infant for unusual bruising or bleeding. One author recommends monitoring infant serum valproate levels, platelets and liver enzymes during therapy.[1] Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions.

Drug Levels

In published reports of anticonvulsant use during breastfeeding, most women were taking a combination of anticonvulsants. Some other anticonvulsants (e.g., phenytoin, carbamazepine) stimulate the metabolism of other drugs including anticonvulsants, whereas others (e.g., valproic acid) inhibit the metabolism of other drugs. Therefore, the relationship of the maternal dosage to the concentration in breastmilk can be quite variable, making calculation of the weight-adjusted percentage of maternal dosage less meaningful than for other drugs in this database.

Divalprox is the chemical combination of 2 valproic acid molecules that results in valproic acid in the bloodstream. Although divalproex has not been studied during breastfeeding, its properties are expected to be identical to those of valproic acid with respect to breastfeeding.

Maternal Levels. An epileptic mother was taking valproic acid 2.4 g daily and primidone 250 mg 3 times daily during pregnancy and postpartum. During the second week postpartum, a breastmilk valproic acid level was 7 mg/L, which was 7% of her serum level.[2]

An epileptic mother was taking valproic acid 1.6 g daily in divided doses. The breastmilk level at 5 days postpartum was 7.2 mg/L; by 29 days postpartum, it had fallen to 3 mg/L.[3]

A woman was taking valproic acid 250 mg twice daily during pregnancy and postpartum. At 62 hours postpartum (16 hours after her last dose) she had a milk level of 180 mcg/L. At 130 hours postpartum (3 hours after her last dose) she had a milk level of 460 mcg/L.[4]

A woman taking valproic acid 250 mg twice daily had milk valproate levels of 2 mg/L 30 minutes after taking a dose. The milk level fell to 0.43 mg/L 1 hour later and to undetectable levels (<0.4 mg/L) an hour after that.[5]

The valproic acid level in the breastmilk of mothers 5 mothers taking valproic acid ranged between 0.4 to 3.9 mg/L. The dosages they were receiving was not stated, but milk levels ranged between 1.3 and 7.1% of the maternal plasma level.[6] This case series was extended to 16 women taking an average of 22.1 mg/kg daily of valproic acid. They had average milk valproate levels of 1.8 mg/L.[7]

In 6 women taking valproic acid in dosages ranging from 9.6 to 31 mg/kg daily, milk valproate levels ranged from 0.034 to 5.4 mg/L and levels of the metabolite 3-keto-valproate ranged from 0.04 to 0.48 mg/L.[8] Extension of the study to 13 patients did not markedly alter the results.[9]

Four women taking valproic acid (1 took 1.2 g daily and 3 took 1.5 g daily)had breastmilk valproate levels measured. Specific milk concentrations are not given, but milk levels were 50 to 10% of maternal serum levels, consistent with other studies. The authors estimated that a breastfed infant would receive only 6 mg in a liter of milk.[10]

Four mothers taking valproic acid (3 took 1.2 g daily and 1 took 1.8 g daily) during pregnancy and postpartum had breastmilk levels measured during the first week postpartum. The average breastmilk levels were 1.8 mg/L (range 1 to 3.8 mg/L).[11]

One woman taking valproic acid 1 g daily had milk levels of 3, 2.3 and 1.4 mg/L on postpartum days 6, 7, and 17, respectively. Another woman was taking valproic acid 1.4 g plus carbamazepine 600 mg and diazepam 2 mg daily. Milk valproate levels were 2, 1.4, 3.5, 2.3 and 2.8 mg/L on postpartum days 1, 3, 15, 29, and 43, respectively.[12]

Infant Levels. The breastfed infant of an epileptic mother who was taking valproic acid 1.6 g daily in divided doses had serum valproic acid level of about 7.5 mg/L on day 5 of life that fell to undetectable levels by day 29.[3]

A 2-month-old breastfed infant was nursed by a mother taking valproic acid 250 mg twice daily. Infant serum levels were undetectable (<0.4 mg/L) before nursing and reached a peak of 2 mg/L 30 minutes after nursing which was 2 hours after the mother's dose. The serum level fell to 1 mg/L 1.5 hours later.[5]

The infant of a mother who was taking valproic acid monotherapy 600 mg twice daily had a serum valproic acid level of 6.6 mg/L.[13]

Two infants were studied whose mothers were taking valproic acid monotherapy for bipolar disorder. A 1-month-old infant had a serum valproate level of 4 mg/L during maternal therapy with 750 mg daily in divided doses. Another fully breastfed 3-month-old whose mother was taking 250 mg of valproic acid twice daily had a serum level of 1 mg/L.[14]

Two breastfed infants whose mothers were taking valproic acid 500 mg daily for bipolar disorder had undetectable (<3.5 and <5 mcg/L) serum valproate levels. Both mothers were also taking clonazepam; one was also taking trifluoperazine and the other was taking fluoxetine.[15]

Four exclusively breastfed infants whose mothers began taking valproic acid monotherapy postpartum in dosages of 750 or 1000 mg daily had average serum levels of 1 mg/L which averaged 1.8% of their mothers' serum levels. Another infant that was 80% breastfed during maternal treatment with 1 g daily had a serum level of 0.7 mg/L or 1% of the maternal serum level. A sixth infant that was 50% breastfed during maternal treatment with 1 g daily had a serum level of 0.7 mg/L or 1.2% of the maternal serum level. All infant serum levels were taken between 4 and 19 weeks of age.[16]

Effects in Breastfed Infants

An epileptic mother was taking valproic acid 2.4 g daily and primidone 250 mg 3 times daily during pregnancy and postpartum. During the second week postpartum, her breastfed infant was sedated. Breastfeeding was stopped and the drowsiness cleared.[2] The sedation was possibly caused by primidone in breastmilk although valproic acid might have contributed by increasing primidone levels.

Petechiae, thrombocytopenia, anemia, and mild hematuria occurred in a 2.5-month-old breastfed infant whose mother was taking valproic acid 600 mg twice daily. The petechiae resolved 8 days after discontinuing breastfeeding. The authors believed the adverse effect to be caused by valproic acid in breastmilk.[13] However, other authors believe that these symptoms were more likely caused by idiopathic thrombocytopenic purpura following a viral infection.[16]

Two breastfed infants aged 1 and 3 months whose mothers were taking valproic acid monotherapy 750 and 500 mg daily developed normally and had no abnormal laboratory values. Their plasma levels were 6% and 1.5% or their mother's serum levels, respectively.[14]

Six breastfed infants whose mothers were taking valproic acid 750 or 1000 mg daily had no adverse reactions to valproic acid in breastmilk.[16]

An exclusively breastfed infants whose mother was taking valproate 1.8 g, topiramate 300 mg, and levetiracetam 2 g, daily during pregnancy and lactation appeared healthy to the investigators throughout the 6- to 8-week study period.[17]

In a long-term study on infants exposed to anticonvulsants during breastfeeding, no difference in average intelligence quotient at 3 years of age was found between infants who were breastfed (n = 11) and those not breastfed (n = 24) when their mothers were taking valproate.[18]

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

References

1. Stowe ZN. The use of mood stabilizers during breastfeeding. J Clin Psychiatry. 2007;68 Suppl 9:22-8. PMID: 17764381

2. Espir MLE, Benton P, Will E et al. Sodium valproate (Epilim) - some clinical and pharmacological aspects. In: Legg NJ, ed. Clinical and pharmacological aspects of sodium valproate in the treatment of epilepsy: proceedings of a symposium. 1976;145-51.

3. Alexander FW. Sodium valproate and pregnancy. Arch Dis Child. 1979;54:240. Letter. PMID: 373647

4. Dickinson RG, Harland RC, Lynn RK et al. Transmission of valproic acid (Depakene) across the placenta: half-life of the drug in mother and baby. J Pediatr. 1979;94:832-5. PMID: 376803

5. Bardy AH, Granstrom M-L, Hiilesmaa VK. Valproic acid and breast-feeding. In: Janz D, Bossi L, Dam M et al., eds. Epilepsy, pregnancy and the child. New York: Raven Press, 1982:359-60.

6. Froescher W, Eichelbaum M, Niesen M et al. Antiepileptic therapy with carbamazepine and valproic acid during pregnancy and lactation period. In: Dam M, ed. Advances in epileptology: XIIth epilepsy international symposium. New York: Raven Press, 1981:581-8.

7. von Unruh GE, Froescher W, Hoffmann F et al. Valproic acid in breast milk: how much is really there? Ther Drug Monit. 1984;6:272-6. PMID: 6438834

8. Nau H, Rating D, Koch S et al. Valproic acid and its metabolites: placental transfer, neonatal pharmacokinetics, transfer via mother's milk and clinical status in neonates of epileptic mothers. J Pharmacol Exp Ther. 1981;219:768-77. PMID: 6795343

9. Nau H, Helge H, Luck W. Valproic acid in the perinatal period: decreased maternal serum protein binding results in fetal accumulation and neonatal displacement of the drug and metabolites. J Pediatr. 1984;104:627-34. PMID: 6423793

10. Philbert A, Pedersen B, Dam M. Concentration of valproate during pregnancy, in the newborn and in breast milk. Acta Neurol Scand. 1985;72:460-3. PMID: 3936331

11. Meyer FP, Quednow B, Potrafki A et al. [The perinatal pharmacokinetics of anticonvulsant drugs]. Zentralbl Gynakol. 1988;110:1195-205. PMID: 3239295

12. Tsuru N, Maeda T, Tsuruoka M. Three cases of delivery under sodium valproate-placental transfer, milk transfer and probable teratogenicity of sodium valproate. Jpn J Psychiatry Neurol. 1988;42:89-96. PMID: 3135429

13. Stahl MM, Neiderud J, Vinge E. Thrombocytopenic purpura and anemia in a breast-fed infant whose mother was treated with valproic acid. J Pediatr. 1997;130:1001-3. PMID: 9202628

14. Wisner KL, Perel JM. Serum levels of valproate and carbamazepine in breastfeeding mother-infant pairs. J Clin Psychopharmacol. 1998;18:167-9. PMID: 9555601

15. Birnbaum CS, Cohen LS, Bailey JW et al. Serum concentrations of antidepressants and benzodiazepines in nursing infants: a case series. Pediatrics. 1999;104:e11. PMID: 10390297

16. Piontek CM, Baab S, Peindl KS et al. Serum valproate levels in 6 breastfeeding mother-infant pairs. J Clin Psychiatry. 2000;61:170-2. PMID: 10817100

17. Johannessen SI, Helde G, Brodtkorb E. Levetiracetam concentrations in serum and in breast milk at birth and during lactation. Epilepsia. 2005;46:775-7. PMID: 15857447

18. Meador KJ, Baker GA, Browning N et al. Effects of breastfeeding in children of women taking antiepileptic drugs. Neurology. 2010;75:1954-60. PMID: 21106960