Valproic acid - Drug Monograph

Introduction

Valproic acid (VPA) is a broad-spectrum anticonvulsant medication first approved in the United States in 1978. It is a branched-chain carboxylic acid that has become a mainstay in the treatment of various seizure disorders and is also widely used as a mood stabilizer in psychiatric practice. Valproic acid and its derivatives (notably divalproex sodium, a stable coordination compound of sodium valproate and valproic acid) represent one of the most commonly prescribed antiepileptic drugs worldwide.

Mechanism of Action

Valproic acid exhibits multiple mechanisms of action that contribute to its therapeutic effects:

• GABAergic enhancement: Increases brain concentrations of gamma-aminobutyric acid (GABA) by inhibiting GABA transaminase and succinic semialdehyde dehydrogenase, thereby enhancing inhibitory neurotransmission
• Voltage-gated sodium channel modulation: Prolongs the inactivated state of voltage-dependent sodium channels, reducing neuronal excitability
• Calcium channel modulation: Blocks T-type calcium channels
• Histone deacetylase inhibition: May contribute to its effects on gene expression and neuroprotection
• Glutamate NMDA receptor antagonism: Modulates excitatory neurotransmission

This multimodal mechanism underlies its efficacy in both seizure disorders and mood stabilization.

Indications

• Monotherapy and adjunctive therapy for complex partial seizures
• Monotherapy and adjunctive therapy for simple and complex absence seizures
• Adjunctive therapy for multiple seizure types including absence seizures
• Treatment of manic episodes associated with bipolar disorder
• Migraine prophylaxis

• Other seizure types (myoclonic, tonic-clonic)
• Neuropathic pain syndromes
• Agitation in dementia
• Borderline personality disorder

Dosage and Administration

• Immediate-release tablets/capsules: 125 mg, 250 mg, 500 mg
• Enteric-coated tablets (divalproex sodium): 125 mg, 250 mg, 500 mg
• Extended-release tablets: 250 mg, 500 mg
• Sprinkle capsules: 125 mg
• Injectable solution: 100 mg/mL
• Oral solution: 250 mg/5 mL

• Epilepsy: Initial dose 10-15 mg/kg/day, increase by 5-10 mg/kg/week to maximum 60 mg/kg/day
• Bipolar disorder: Initial dose 750 mg/day in divided doses, titrate to 1000-1500 mg/day
• Migraine prophylaxis: Initial dose 250 mg twice daily, titrate to 1000 mg/day

• Geriatric: Start with lower doses due to decreased clearance
• Hepatic impairment: Contraindicated in significant hepatic disease
• Renal impairment: Dose adjustment may be necessary; monitor carefully
• Pediatric: Dose based on weight (20-30 mg/kg/day initially)

Pharmacokinetics

• Absorption: Rapid and complete with food delaying but not decreasing absorption
• Distribution: Volume of distribution 0.13-0.23 L/kg; highly protein bound (80-90%)
• Metabolism: Extensive hepatic metabolism via glucuronidation, β-oxidation, and cytochrome P450 pathways
• Elimination: Half-life 9-16 hours; primarily renal excretion of metabolites
• Therapeutic range: 50-100 μg/mL for epilepsy; 50-125 μg/mL for bipolar disorder

Contraindications

• Known hypersensitivity to valproic acid or its components
• Hepatic disease or significant hepatic dysfunction
• Known urea cycle disorders
• Mitochondrial disorders caused by POLG mutations
• Pregnancy (for migraine prophylaxis)

Warnings and Precautions

1. Hepatotoxicity: Fatal hepatic failure reported, especially in children under 2 years and those with metabolic disorders 2. Teratogenicity: Neural tube defects and other major malformations reported 3. Pancreatitis: Life-threatening cases reported, can occur at any time during treatment

• Thrombocytopenia and other hematologic abnormalities
• Hyperammonemia with or without encephalopathy
• Somnolence in elderly patients with dementia
• Suicidal thoughts and behavior
• Weight gain and metabolic syndrome
• Polycystic ovary syndrome in women

Drug Interactions

• Enzyme inducers (carbamazepine, phenytoin, rifampin): Decrease valproate levels
• Enzyme inhibitors (felbamate): Increase valproate levels
• Protein displacement interactions (aspirin, warfarin): Increase free fraction of either drug
• CNS depressants: Enhanced sedative effects
• Lamotrigine: Valproate increases lamotrigine levels and risk of serious rash
• Phenobarbital: Mutual effects on metabolism
• Zidovudine: Valproate may increase zidovudine levels

Adverse Effects

• Nausea, vomiting, diarrhea
• Drowsiness, dizziness
• Tremor
• Weight gain
• Alopecia (usually reversible)

• Hepatotoxicity (monitor LFTs)
• Pancreatitis
• Thrombocytopenia
• Hyperammonemic encephalopathy
• Stevens-Johnson syndrome
• Cognitive impairment
• Birth defects

Monitoring Parameters

• Complete blood count with platelets
• Liver function tests
• Pregnancy test in women of childbearing potential
• Ammonia level if symptoms suggest hyperammonemia

• Serum drug levels (especially with dose changes or clinical concerns)
• LFTs every 3-6 months initially, then annually if stable
• CBC with platelets periodically
• Ammonia level if mental status changes occur
• Weight and metabolic parameters regularly
• Therapeutic drug monitoring: 50-100 μg/mL for most indications

• Women of childbearing potential: contraceptive counseling and folate supplementation
• Elderly patients: cognitive and functional assessment

Patient Education

• Take with food to minimize gastrointestinal upset
• Do not crush or chew enteric-coated tablets
• Swallow capsules whole; sprinkle capsules may be opened and contents sprinkled on soft food
• Avoid alcohol consumption
• Report any signs of liver problems (nausea, vomiting, abdominal pain, jaundice)
• Report any signs of pancreatitis (severe abdominal pain, nausea, vomiting)
• Use effective contraception; discuss pregnancy planning with provider
• Be aware of potential for drowsiness, especially when driving or operating machinery
• Do not abruptly discontinue medication
• Regular laboratory monitoring is essential
• Wear medical alert identification indicating anticonvulsant use

References

1. FDA Prescribing Information: Depakote (divalproex sodium) 2. Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551-563. 3. Johannessen CU, Johannessen SI. Valproate: past, present, and future. CNS Drug Rev. 2003;9(2):199-216. 4. Muralidharan A, Bhagwagar Z. Potential of valproate in the treatment of bipolar disorder. CNS Drugs. 2006;20(5):389-404. 5. Nanau RM, Neuman MG. Adverse drug reactions induced by valproic acid. Clin Biochem. 2013;46(15):1323-1338. 6. Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs. 2002;16(10):695-714. 7. Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011;10(7):609-617. 8. American Epilepsy Society. Clinical practice guideline: use of valproate in women and girls of childbearing potential. Epilepsy Currents. 2019;19(2):117-125.