Valproic Acid

Name: Valproic Acid

What Is Valproic Acid?

Valproic acid affects chemicals in the body that may be involved in causing seizures.

Valproic acid is used to treat various types of seizure disorders. Valproic acid is sometimes used together with other seizure medications.

Valproic acid is also used to treat manic episodes related to bipolar disorder (manic depression), and to prevent migraine headaches.

Valproic acid may also be used for purposes not listed in this medication guide.

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

If you take valproic acid for seizures or manic episodes: Do not start or stop taking the medicine during pregnancy without your doctor's advice.

You should not use valproic acid if you have liver disease, a urea cycle disorder, or a genetic disorder such as Alpers' disease or Alpers-Huttenlocher syndrome (especially in a child younger than 2 years old).

Valproic acid 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 (MYE-toe-KON-dree-al) disorder.

Call your doctor at once if the person taking this medicine has signs of liver or pancreas problems, such as: loss of appetite, upper stomach pain (that may spread to your back), ongoing nausea or vomiting, dark urine, swelling in the face, or jaundice (yellowing of the skin or eyes).

You should not use valproic acid if you are allergic to it, 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.

Valproic acid 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 valproic acid 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 valproic acid. 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 valproic acid to prevent migraine headaches if you are pregnant.

If you take valproic acid 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 valproic acid during pregnancy without your doctor's advice.

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

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

Valproic acid can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine.

Valproic Acid Interactions

Drinking alcohol may increase certain side effects of valproic acid.

Valproic acid may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid exposure to sunlight or tanning beds. Valproic acid can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Other drugs may interact with valproic acid, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Side effects

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

  • Hepatic failure [see WARNINGS AND PRECAUTIONS]
  • Birth defects [see WARNINGS AND PRECAUTIONS]
  • Decreased IQ following in utero exposure [see WARNINGS AND PRECAUTIONS]
  • Pancreatitis [see WARNINGS AND PRECAUTIONS]
  • Hyperammonemic encephalopathy [see WARNINGS AND PRECAUTIONS]
  • Suicidal behavior and ideation [see WARNINGS AND PRECAUTIONS]
  • Bleeding and other hematopoietic disorders [see WARNINGS AND PRECAUTIONS]
  • Hypothermia [see WARNINGS AND PRECAUTIONS]
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
  • Somnolence in the elderly [see WARNINGS AND PRECAUTIONS]

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.

Epilepsy

The data described in the following section were obtained using Depakote (divalproex sodium) tablets.

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 Depakotetreated patients (6%), compared to 1% of placebo-treated patients.

Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakotetreated patients and for which the incidence was greater than in the placebo group, in a placebo-controlled trial of adjunctive therapy for the 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 3: Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures

Body System/Reaction Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
  Headache 31 21
  Asthenia 27 7
  Fever 6 4
Gastrointestinal System
  Nausea 48 14
  Vomiting 27 7
  Abdominal Pain 23 6
  Diarrhea 13 6
  Anorexia 12 0
  Dyspepsia 8 4
  Constipation 5 1
Nervous System
  Somnolence 27 11
  Tremor 25 6
  Dizziness 25 13
  Diplopia 16 9
  Amblyopia/Blurred Vision 12 9
  Ataxia 8 1
  Nystagmus 8 1
  Emotional Lability 6 4
  Thinking Abnormal 6 0
  Amnesia 5 1
Respiratory System
  Flu Syndrome 12 9
  Infection 12 6
  Bronchitis 5 1
  Rhinitis 5 4
Other
  Alopecia 6 1
  Weight Loss 6 0

Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose Depakote 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 Depakote and other antiepilepsy drugs.

Table 4: Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Depakote Monotherapy for Complex Partial Seizures1

Body System/Reaction High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
  Asthenia 21 10
Digestive System
  Nausea 34 26
  Diarrhea 23 19
  Vomiting 23 15
  Abdominal Pain 12 9
  Anorexia 11 4
  Dyspepsia 11 10
Hemic/Lymphatic System
  Thrombocytopenia 24 1
  Ecchymosis 5 4
Metabolic/Nutritional
  Weight Gain 9 4
  Peripheral Edema 8 3
Nervous System
  Tremor 57 19
  Somnolence 30 18
  Dizziness 18 13
  Insomnia 15 9
  Nervousness 11 7
  Amnesia 7 4
  Nystagmus 7 1
  Depression 5 4
Respiratory System
  Infection 20 13
  Pharyngitis 8 2
  Dyspnea 5 1
Skin and Appendages
  Alopecia 24 13
Special Senses
  Amblyopia/Blurred Vision 8 4
  Tinnitus 7 1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group.

The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with Depakote 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.

Mania

Although Depakene has not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote tablets.

Body as a Whole: Chills, neck pain, neck rigidity.

Cardiovascular System: Hypotension, postural hypotension, vasodilation.

Digestive System: Fecal incontinence, gastroenteritis, glossitis.

Musculoskeletal System: Arthrosis.

Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.

Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.

Special Senses: Conjunctivitis, dry eyes, eye pain.

Urogenital System: Dysuria.

Migraine

Although Depakene has not been evaluated for safety and efficacy in the treatment of prophylaxis of migraine headaches, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote tablets.

Body as a Whole: Face edema.

Digestive System: Dry mouth, stomatitis.

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: 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, leucopenia, 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.

Clinical pharmacology

Mechanism Of Action

Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its antiepileptic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).

Pharmacodynamics

The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species.

For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.

Epilepsy

The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations.

Pharmacokinetics

Absorption/Bioavailability

Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy.

However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).

While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint.

Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see DOSAGE AND ADMINISTRATION]. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations.

Distribution

Protein Binding

The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide). (See DRUG INTERACTIONS for more detailed information on the pharmacokinetic interactions of valproate with other drugs.)

CNS Distribution

Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration).

Metabolism

Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.

The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.

Elimination

Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m² and 11 L/1.73 m², respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m² and 92 L/1.73 m². Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.

The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn.

Special Populations

Effect of Age

Neonates

Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months.

Children

Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.

Elderly

The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see DOSAGE AND ADMINISTRATION].

Effect of Sex

There are no differences in the body surface area adjusted unbound clearance between males and females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m², respectively).

Effect of Race

The effects of race on the kinetics of valproate have not been studied.

Effect of Disease

Liver Disease

[See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS]. Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.

Renal Disease

A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.

Clinical Studies

The studies described in the following section were conducted using Depakote (divalproex sodium) tablets.

Epilepsy

The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials.

In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the “therapeutic range” were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings.

Table 5: Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks

Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence
Depakote 75 16.0 8.9*
Placebo 69 14.5 11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤ 0.05 level.

Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for Depakote than for placebo. For example, 45% of patients treated with Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo.

Figure 1

The second study assessed the capacity of Depakote to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to Depakote. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively.

The following Table presents the findings for all patients randomized who had at least one post-randomization assessment.

Table 6: Monotherapy Study Median Incidence of CPS per 8 Weeks

Treatment Number of Patients Baseline Incidence Randomized Phase Incidence
High dose Depakote 131 13.2 10.7*
Low dose Depakote 134 14.2 13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.

Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose Depakote than for low dose Depakote. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose Depakote.

Figure 2

REFERENCES

1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12 (3):244-252.

Overdose

Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.

Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.

  • Seizure (Epilepsy)
  • Sleep Disorder Drugs

What is the most important information i should know about valproic acid (depakene, stavzor)?

Do not start or stop taking valproic acid during pregnancy without your doctor's advice. Valproic acid may cause harm to an unborn baby, but having a seizure during pregnancy could harm both the mother and the baby. Tell your doctor right away if you become pregnant while taking valproic acid for seizures.

In rare cases, valproic acid has caused life-threatening liver failure, especially in children younger than 2 years old.

Valproic acid has also caused rare cases of life-threatening pancreatitis (inflammation of the pancreas). Pancreatitis can come on suddenly and symptoms may start even after you have been taking valproic acid for several years.

Seek emergency medical attention if the person taking this medicine has nausea, vomiting, upper stomach pain, or loss of appetite, low fever, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes). These symptoms may be early signs of liver damage. Some of these symptoms may also be early signs of pancreatitis.

You may have thoughts about suicide while taking this medication. Your doctor will need to check you at regular visits. Do not miss any scheduled appointments.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, depression, anxiety, or if you feel agitated, hostile, restless, hyperactive (mentally or physically), or have thoughts about suicide or hurting yourself.

What is the most important information I should know about valproic acid?

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

If you take valproic acid for seizures or manic episodes: Do not start or stop taking the medicine during pregnancy without your doctor's advice.

You should not use valproic acid if you have liver disease, a urea cycle disorder, or a genetic disorder such as Alpers' disease or Alpers-Huttenlocher syndrome (especially in a child younger than 2 years old).

Valproic acid 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 (MYE-toe-KON-dree-al) disorder.

Call your doctor at once if the person taking this medicine has signs of liver or pancreas problems, such as: loss of appetite, upper stomach pain (that may spread to your back), ongoing nausea or vomiting, dark urine, swelling in the face, or jaundice (yellowing of the skin or eyes).

What should I avoid while taking valproic acid?

Drinking alcohol may increase certain side effects of valproic acid.

Valproic acid may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid exposure to sunlight or tanning beds. Valproic acid can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Stability

Storage

Oral

Capsules

Valproic acid: Tight containers at 15–30°C.b Depakene: Tight containers at 15–25°C.184 b Stavzor: 25°C; may be exposed to 15–30°C.214

Divalproex sodium capsules containing coated particles (Depakote Sprinkle): <25°C.179 b

Tablets

Divalproex sodium delayed-release tablets: Tight, light-resistant containers at a temperature <30°C.b

Divalproex sodium extended-release tablets: 25°C, but may be exposed to temperatures ranging from 15–30°C.182

Solution

Valproate sodium: Tight containers at <30°C; avoid freezing.184 b

Parenteral

Injection

15–30°C.185 b

Discard unused portions of the solution.185 b

When stored in glass or PVC containers at 15–30°C, injection that has been further diluted with at least 50 mL of 5% dextrose injection, 0.9% sodium chloride injection, or lactated Ringer’s injection is stable for at least 24 hours.185 b

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility185 HID

Compatible

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.9%

Drug CompatibilityHID Y-Site CompatibilityHID

Compatible

Cefepime HCI

Ceftazidime

(web3)