Valproic Acid

From Anvita Health Wiki

Contents 1 Introduction 2 Indications 3 Contraindications 4 Dosage 5 Pharmacokinetics 6 Monitor 7 Adverse-effects 8 Drug-interactions 9 Laboratory 10 Mechanism-of-action 11 More General Terms 12 Additional Terms 13 Internet Database 14 References

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 headaches
• mood disorders

Contraindications

• pregnancy (relative contraindication) [13,14] pregnant women using valproate or other anticonvulsants should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry [16]
  

• 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 [10] 8-20% larger dose of Depakote ER required for similar serum level [10]

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 [8,15]
• plasma ammonia in the event of lethargy, vomiting, mental status change, hypothermia [15]
  
• monitor with anticonvulsants

Adverse-effects

• most common (1-10%)

• abdominal cramps, anorexia, diarrhea, nausea/vomiting, change in menstrual cycle, weight gain

• uncommon (< 1%)

• drowsiness, ataxia, tremor, irritability, confusion, restlessness, hyperactivity, malaise, headache, alopecia, erythema multiforme, hyperammonemia, pancreatitis, thrombocytopenia*, prolongation of bleeding time, transient increases in serum transaminases, liver failure, nystagmus, seeing spots, photosensitivity

• other

• osteoporosis [5]

• in utero exposure [11]

• fetal valproate syndrome
• increase risk of autism [11]
• cognitive impairment [12]
• craniofacial defects

• cleft palate (5.2)
• craniosynostosis (6.8)

• atrial septal defect (2.5)
• hypospadias (4.8)
• polydactyly (2.2) [14]

• * thrombocytopenia may be more common than 1% [9]
  

• drug adverse effects of anticonvulsants

Drug-interactions

• do NOT give with clonazepam
• carbamazepine

• increased carbamazepine metabolites (including active 9,10 epoxide) [9]
• 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

Laboratory

• specimen:

• 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
• carboxylate
• histone decetylase inhibitor

Additional Terms

• fetal valproate syndrome
• valproic acid in serum/plasma

Internet Database

PubChem: 3121
PubChem: 147515
PubChem: 86480
PubChem: 53519
PubChem: 14047

References

1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
2. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 701
3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
4. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
5. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, American College of Physicians, Philadelphia 1998, 2009
6. Prescriber's Letter 7(9):53 2000
7. Clinical Guide to Laboratory Tests, NW Tietz (ed) 3rd ed, WB Saunders, Philadelpha 1995
8. Prescriber's Letter 8(8):48, 2001
9. Small G. In:Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
10. Prescriber's Letter 10(2):8 2003
11. Bromley RL et al. Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology 2008 Dec 2; 71:1923. PMID: [1]
12. Meador KJ et al Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009 Apr 16; 360:1597 PMID: [2]
    - Tomson T. Which drug for the pregnant woman with epilepsy? N Engl J Med 2009 Apr 16; 360:1667. PMID: [3]
13. FDA MedWatch Valproate Sodium and related products (valproic acid and divalproex sodium): Risk of Birth Defects [4]
14. Jentink J et al Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations N Engl Med Volume 362:2185-2193, 2010 [5]
15. Anvita Health guideline :id 1651 Anvita Health guideline :id 1652
    - Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: [6] (subscription needed) [7]
16. Fleisher AS et al. Chronic divalproex sodium use and brain atrophy in Alzheimer disease. Neurology 2011 Sep 27; 77:1263. PMID: [8]
17. North American Antiepileptic Drug (NAAED) Pregnancy Registry
18. National Guideline Clearinghouse Valproic acid poisoning: an evidence-based consensus guideline for out-of-hospital management. (American Association of Poison Control Center) ngc-guideline: [9]

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