Valproic acid

Class
Anticonvulsants
Subclass
Valeric acid derivatives
Substance name
Valproic acid, VPA
Common formulations
Capsule, Solution
Dosage and administration
Adults patients
Treatment
Absence seizures • Simple or complex
•
Start at: 15 mg/kg PO daily
•
Maximum: 60 mg/kg per day
Titrate in 5-10 mg/kg increments weekly until seizures are controlled or side effects preclude further increases. Administer daily doses exceeding 250 mg in divided doses.
Complex partial seizures
•
Start at: 10-15 mg/kg PO daily
•
Maximum: 60 mg/kg per day
Titrate in 5-10 mg/kg increments weekly to response. Administer daily doses exceeding 250 mg in divided doses. Measure plasma levels in cases of unsatisfactory clinical response to determine whether the values are within the therapeutic range (50-100 mcg/mL).
Acute mania in patients with bipolar disorder • Off-label
•
15-20 mg/kg PO daily, in 2 divided doses
Bipolar disorder • Maintenance therapy • Off-label
•
1,000-3,000 mg PO daily
Titrate to serum level of 50-125 mcg/mL.
Catatonia • Off-label
•
600-4,000 mg PO daily
Diabetic neuropathy • Off-label
•
1,000-1,200 mg PO daily for 4-12 weeks
Adjunctive treatment
Adjunctive treatment for alcohol withdrawal syndrome • Off-label
•
300-500 mg PO q6-8h
Administered in combination with benzodiazepines.
Other off-label uses
•
Treatment of depressive episodes in patients with bipolar disorder
•
Treatment of depressive episodes in patients with bipolar disorder (monotherapy)
Indications for use
Labeled indications
Adults
•
Treatment of absence seizures (simple or complex)
•
Treatment of complex partial seizures
Off-label indications
Adults
•
Treatment of acute mania in patients with bipolar disorder
•
Treatment of bipolar disorder (maintenance therapy)
•
Treatment of catatonia
•
Treatment of depressive episodes in patients with bipolar disorder
•
Treatment of depressive episodes in patients with bipolar disorder (monotherapy)
•
Treatment of diabetic neuropathy
•
Adjunctive treatment for alcohol withdrawal syndrome
Safety risks
Boxed warnings
Acute pancreatitis
•
Maintain a high level of suspicion, as valproic acid has been associated with an increased risk of life-threatening pancreatitis.
Hepatotoxicity
•
Maintain a high level of suspicion, as valproic acid has been associated with an increased risk of hepatic failure. Obtain LFTs before treatment and at frequent intervals thereafter, especially during the first 6 months.
•
Use extreme caution in pediatric patients aged < 2 years, especially with congenital metabolic disorders, severe seizure disorders accompanied by mental retardation, organic brain disease, or receiving multiple anticonvulsants.
•
Do not use in patients with mitochondrial disease caused by mutations in mitochondrial DNA polymerase γ and in children < 2 years of age with suspected mitochondrial disorder.
Neural tube defects
•
The use of valproic acid during pregnancy has been associated with an increased risk of major congenital malformations, particularly neural tube defects, other structural abnormalities (craniofacial defects, cardiovascular malformations, hypospadias, limb malformations), neurodevelopmental disorders, and decreased IQ. Do not use valproic acid for epilepsy or bipolar disorder in pregnant patients or patients contemplating pregnancy unless other medications have failed to provide adequate symptom control. Do not use valproic acid for migraine prophylaxis in pregnant patients and in female patients of childbearing potential not using effective contraception. Do not use valproic acid in females of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.
Contraindications
Hypersensitivity to valproic acid or its components
Hepatic disease or significant hepatic dysfunction
Urea cycle disorders
Warnings and precautions
Decreased body temperature
•
Maintain a high level of suspicion, as valproic acid has been associated with an increased risk of hypothermia, both in conjunction with and in the absence of hyperammonemia.
Decreased platelet count, coagulopathy
•
Maintain a high level of suspicion, as valproic acid has been associated with an increased risk of thrombocytopenia and coagulopathy. Obtain CBC and coagulation tests before treatment and at periodic intervals during treatment. Monitor CBC and coagulation parameters before planned surgery.
Decreased serum valproate levels
•
Use caution in patients receiving carbapenem antibiotics. Monitor serum valproate concentrations after initiating carbapenem therapy.
DRESS syndrome
•
Maintain a high level of suspicion, as valproic acid has been associated with an increased risk of DRESS syndrome.
Increased blood ammonia
•
Use caution in patients receiving concomitant topiramate or in patients with inborn errors of metabolism or reduced hepatic mitochondrial activity.
•
Maintain a high level of suspicion, as valproic acid has been associated with an increased risk of hyperammonemia. Suspect hyperammonemia in patients developing unexplained lethargy, vomiting, changes in mental status, or hypothermia.
Increased urine ketones
•
Maintain a high level of suspicion, as valproate is partially eliminated in the urine as a keto-metabolite and may lead to false-positive results in urine ketone tests.
Somnolence
•
Use caution in elderly patients. Titrate slowly with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.
Suicidal ideation
•
Maintain a high level of suspicion, as antiepileptic drugs, including valproic acid, have been associated with an increased risk of suicidal ideation and behavior. Monitor for new or worsening depression, suicidal thoughts/behavior, and/or unusual changes in mood or behavior.
Specific populations
Renal impairment
eGFR 0-90 mL/min/1.73 m²
•
Use acceptable. No dose adjustment required.
Renal replacement therapy
Continuous renal replacement
•
Use acceptable. No dose adjustment required.
Intermittent hemodialysis
•
Use acceptable. No dose adjustment required.
Peritoneal dialysis
•
Use acceptable. No dose adjustment required.
Hepatic impairment
Any severity
•
Do not use.
Pregnancy and breastfeeding
Pregnancy
All trimesters • Australia Category: D
•
Do not use. Evidence of fetal harm in humans. The use of valproic acid during pregnancy has been associated with an increased risk of major congenital malformations, particularly neural tube defects, other structural abnormalities (craniofacial defects, cardiovascular malformations, hypospadias, limb malformations), neurodevelopmental disorders, and decreased IQ.
•
Do not use valproic acid for epilepsy or bipolar disorder in pregnant patients or patients contemplating pregnancy unless other medications have failed to provide adequate symptom control.
•
Do not use valproic acid for migraine prophylaxis in pregnant patients and in female patients of childbearing potential not using effective contraception.
•
Do not use valproic acid in females of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.
Breastfeeding
Use only if benefits outweigh potential risks.
•
Monitor infants for signs of liver damage and unusual bruising or bleeding.
Low excretion in breastmilk (5-25%).
Low levels in breastfed infants (5-25%).
Unlikely to cause adverse effects in breastfed infants.
Adverse reactions
Very common > 10%
•
↓ platelet count, infections, abdominal pain, asthenia, diarrhea, diplopia, dizziness, hair loss, headache, insomnia, loss of appetite, nausea, somnolence, vomiting, tremor
Common 1-10%
•
Acute cystitis, furuncles, tardive dyskinesia, catatonia, gastroenteritis, acute pancreatitis, periodontal abscess, sinusitis, pneumonia, acute otitis media, vaginitis, ataxia, peripheral edema, pharyngitis, bronchitis, nystagmus, back pain, chest pain, malaise, tachycardia, palpitations, hypertension, flatulence, ↑ appetite, hematemesis, belching, petechiae, ↑ serum ALT, ↑ serum AST, muscle twitching, myalgia, muscle weakness, arthralgia, leg cramps, anxiety, gait disturbance, confusion, paresthesia, incoordination, hypertonia, nightmares, development and personality, cough, nosebleed, skin rash, pruritus, skin dryness, change in taste, hearing loss, visual disturbances, urinary incontinence, dysmenorrhea, urinary frequency, amenorrhea, blurred vision, constipation, depression, dyspnea, rhinitis, ecchymosis, dyspepsia, emotional lability, fever, memory impairment, neck pain, chills, hypotension, nuchal rigidity, skin flushing, orthostatic hypotension, glossitis, fecal incontinence, arthritis, agitation, hypokinesia, hyperreflexia, vertigo, maculopapular rash, conjunctivitis, eye pain, dry eyes, dysuria, dry mouth, facial edema, stomatitis, vaginal bleeding, nervousness, tinnitus, weight gain, weight loss
Unknown frequency
•
Hair discoloration, photosensitivity of skin, erythema multiforme, nail abnormality, aggressive behavior, psychosis, hostility, emotional lability, parkinsonism, seizure, ↑ blood lymphocyte count, macrocytosis, ↓ WBC count, anemia, folate deficiency, pancytopenia, agranulocytosis, menstrual irregularity, ↑ serum testosterone, hirsutism, galactorrhea, breast enlargement, parotid gland enlargement, ↓ serum sodium, ↓ serum carnitine, ↑ blood glucose, azoospermia, male infertility, developmental delay, bradycardia, bone pain, toxic epidermal necrolysis, Stevens-Johnson syndrome, bone fracture, osteopenia, osteoporosis, aplastic anemia, acute intermittent porphyria, syndrome of inappropriate antidiuretic hormone secretion, Fanconi syndrome, urinary tract infections, enuresis, anaphylaxis, cutaneous vasculitis
Interactions
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