valproic acid; n-dipropylacetic acid (Depakene, Depakote, Divalproex, Mylproin, Valontin, Stavzor)

Introduction

Tradenames: Depakene, Depakote, Divalproex, Stavzor. Aliases: VPA, or n-dipropyl-acetic acid.

Indications

• seizures:
  • absence seizures, atypical absence seizures, myoclonic seizures, tonic-clonic seizures, partial seizures
  • the most effective agent for all primary generalized forms of epilepsy
• migraine prophylaxis
• mood disorders, bipolar disorder, mania

Contraindications

• avoid in patients with liver failure
• pregnancy (relative contraindication)
  • contraindicated for preventing migraine headache during pregnancy
  • pregnant women using valproate or other anticonvulsants should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry
  • in UK, valproate banned for women of childbearing age unless enrolled in a pregnancy prevention program
  • increased risk of autism in offspring
• men taking valproate should use contraception & for 3 months & after stopping due to small potential risk of neurodevelopmental disorders in conceived offspring
• ineffective in treating psychosis & agitation in the elderly
  • results in cognitive decline

pregnancy category = d

safety in lactation = ?

Dosage

• start 15 mg/kg/day PO divided BID or TID
• increase by 5-10 mg/kg/day at weekly intervals until seizures are controlled
• maximum: 60 mg/kg/day
• dose should be divided BID or TID to prevent GI side effects
• Depakote ER: 500-1000 mg PO QD

Tabs: 125, 250, 500 mg.

Syrup: 250 mg/5 mL.

Injection: 100 mg/mL (5 mL).

Depakote ER: 250 & 500 mg tabs (Stavzor)

• NOT bioequivalent* to Depakote

* Depakote ER results in lower serum levels than Depakote 8-20% larger dose of Depakote ER required for similar serum level

Dosage adjustment in renal failure

• none
• supplemental dose after dialysis uncertain

Pharmacokinetics

• oral dose is rapidly absorbed
• absorption of enteric coated tablet is delayed by about 1 hour
• 84-90% bound to plasma proteins
• metabolized by the liver
• excreted in the urine
• elimination 1/2life is 5-20 hours
• therapeutic plasma levels are 50-100 ug/mL

elimination via liver

1/2life = 8-15 hours

protein binding = 84-90 %

elimination by hemodialysis = -

elimination by peritoneal dialysis = -

Monitor

• complete blood count (CBC)
• platelet count & coagulation tests (PT, PTT, INR)
  • periodically
  • prior to planned surgery
  • during pregnancy
• liver function tests baseline & frequently, especially during the first 6 months of treatment
  • every 6 months
• plasma ammonia in the event of lethargy, vomiting, mental status change, hypothermia

• monitor with anticonvulsants

Adverse effects

• most common (1-10%)
  • abdominal cramps, anorexia, diarrhea, nausea/vomiting, change in menstrual cycle, weight gain, tremor, hirsuitism, alopecia, hyperammonemia
• uncommon (< 1%)
  • drowsiness, ataxia, irritability, confusion, restlessness, hyperactivity, malaise, headache, erythema multiforme, transient elevated serum transaminases, nystagmus, seeing spots, photosensitivity
• serious
  • hepatotoxicity, liver failure, pancreatitis
  • thrombocytopenia*, platelet dysfunction, aplastic anemia
• other
  • osteoporosis
  • cognitive decline
  • hypercholesterolemia
  • polycystic ovary syndrome
• in utero exposure
  • teratogenic
  • fetal valproate syndrome
  • increase risk of autism
  • cognitive impairment
    • maternal use of valproate associated a decrease in school performance in offspring compared with children unexposed to anticonvulsants & children exposed to lamotrigine
  • craniofacial defects
    • cleft palate (5.2)
    • craniosynostosis (6.8)
  • atrial septal defect (2.5)
  • hypospadias (4.8)
  • polydactyly (2.2)
  • major congenital malformations: among anticonsulsants valproate with highest risk (25% >1450 mg/day)
  • 40% risk of developmental disorder
• increased risk of Parkinson's disease (RR~1.8)

* thrombocytopenia may be more common than 1%

• drug adverse effects of anticonvulsants
• drug adverse effects of psychotropic agents

Drug interactions

• do NOT give with clonazepam
• carbamazepine
  • increased carbamazepine metabolites (including active 9,10 epoxide)
  • decreased valproate levels
• phenytoin
  • increased free phenytoin
  • decreased valproate levels
• phenobarbital:
  • increased phenobarbital levels
  • increased CNS effects
• chlorpromazine, cimetidine, aspirin: increased valproate levels
• warfarin: increased risk of bleeding
• rifampin: decreased valproate levels Interactions:
  • potential interactions with voltage sensitive Na+ channels & possible enhancement of GABA accumulation

• drug interaction(s) anticonvulsants with anti-bacterial agents
• drug interaction(s) anticonvulsants with statins

Laboratory

• valproic acid in serum/plasma:
  • serum, plasma (EDTA)
  • stable at room temperature for several hours
  • stable for 1 year at -20 degrees C
• methods: GLC, GC-MS, EIA, FPIA, FIA

Mechanism of action

• unknown
• may be related to increased brain concentrations of GABA
• may inhibit metabolism of GABA
• inhibits inositol-3-phosphate synthase

More general terms

• anticonvulsant
• mood stabilizer
• carboxylate
• histone decetylase inhibitor

Additional terms

• fetal valproate syndrome
• valproic acid in serum/plasma

Component of

• lamotrigine/valproic acid
• carbamazepine/lamotrigine/phenobarbital/phenytoin/primidone/valproic acid

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3121
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=147515
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=86480
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=53519
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=14047