Introduction
Valproate sodium is an anticonvulsant medication belonging to the class of fatty acid derivatives. It is the sodium salt of valproic acid and has been widely used in clinical practice since the 1970s. Valproate sodium represents one of the broad-spectrum antiepileptic drugs with multiple mechanisms of action and therapeutic applications beyond epilepsy management.
Mechanism of Action
Valproate sodium exerts its pharmacological effects through several mechanisms:
- Enhancement of GABAergic neurotransmission by inhibiting GABA transaminase and succinic semialdehyde dehydrogenase, increasing brain GABA levels
- Modulation of voltage-gated sodium channels by prolonging the inactivated state
- Potential action on T-type calcium channels
- Inhibition of histone deacetylases, which may contribute to its effects in mood disorders
- Reduction of excitatory neurotransmission through actions on glutamate receptors
Indications
FDA-approved 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
- Neuropathic pain management
- Aggression and agitation in dementia (with caution)
- Certain psychiatric conditions
Dosage and Administration
Epilepsy:- Adults: Initial dose 10-15 mg/kg/day, increase by 5-10 mg/kg/week
- Maintenance: Usually 1,000-2,500 mg/day in divided doses
- Maximum dose: 60 mg/kg/day
- Initial: 750 mg/day in divided doses
- Increase rapidly to achieve therapeutic response
- Maximum: 60 mg/kg/day
- Initial: 250 mg twice daily
- May increase to 1,000 mg/day
- Geriatric: Start with lower doses due to decreased clearance
- Hepatic impairment: Contraindicated in significant liver disease
- Renal impairment: Use with caution; monitor concentrations
- Oral tablets should be swallowed whole
- May be administered with food to reduce GI upset
- Therapeutic range: 50-100 μg/mL
Pharmacokinetics
Absorption: Rapid and complete with bioavailability >90% Distribution: Volume of distribution 0.13-0.23 L/kg; highly protein bound (80-90%) Metabolism: Extensive hepatic metabolism via glucuronidation and mitochondrial β-oxidation Elimination: Half-life 9-16 hours; primarily renal excretion of metabolites Special considerations: Protein binding becomes saturated at higher concentrationsContraindications
- Known hypersensitivity to valproate sodium or any component
- Hepatic disease or significant hepatic dysfunction
- Known urea cycle disorders
- Mitochondrial disorders caused by POLG mutations
- Pregnancy for migraine prevention
Warnings and Precautions
Black Box Warnings:- Hepatotoxicity: Fatal hepatic failure reported, especially in children under 2 years
- Teratogenicity: Neural tube defects and other major malformations
- Pancreatitis: Life-threatening cases reported
- Thrombocytopenia and other hematologic abnormalities
- Hyperammonemic encephalopathy
- Somnolence in elderly patients
- Suicidal thoughts and behavior
- Weight gain and metabolic effects
Drug Interactions
Major interactions:- Lamotrigine: Decreases lamotrigine clearance
- Phenobarbital, phenytoin: May decrease valproate levels
- Carbapenem antibiotics: Significantly reduce valproate levels
- Warfarin: Alters anticoagulant effect
- Aspirin: Increases free valproate concentration
- CNS depressants: Additive sedative effects
- Drugs highly protein-bound may displace valproate
- Monitor for increased free fraction and toxicity
Adverse Effects
Common (≥10%):- Nausea, vomiting, diarrhea
- Drowsiness, dizziness
- Tremor
- Weight gain
- Alopecia
- Hepatotoxicity
- Pancreatitis
- Thrombocytopenia
- Hyperammonemia
- Stevens-Johnson syndrome
- Cognitive impairment
Monitoring Parameters
Baseline:- Complete blood count with platelets
- Liver function tests
- Pregnancy test in women of childbearing potential
- Ammonia level if symptoms suggest hyperammonemia
- Therapeutic drug monitoring (50-100 μg/mL)
- LFTs every 3-6 months
- CBC with platelets periodically
- Ammonia level if clinically indicated
- Weight and metabolic parameters
- Signs of pancreatitis
- Increased frequency in high-risk populations
- Close monitoring during dosage adjustments
- Enhanced monitoring with concomitant hepatotoxic drugs
Patient Education
Key points to discuss:- Take medication exactly as prescribed
- Do not abruptly discontinue therapy
- Report any signs of liver problems (nausea, vomiting, abdominal pain, jaundice)
- Inform about pregnancy risks and need for contraception
- Report unusual bleeding or bruising
- Be aware of potential drowsiness; avoid driving if affected
- Regular blood tests are necessary
- Maintain consistent dietary habits
- Report any mood changes or suicidal thoughts
- Women of childbearing potential require extensive counseling
- Use effective contraception
- Consider folic acid supplementation
- Report planned pregnancy immediately
References
1. FDA Prescribing Information: Depakote (valproate sodium) 2. Glauser TA, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013. 3. Johannessen CU, Johannessen SI. Valproate: past, present, and future. CNS Drug Reviews. 2003. 4. Mula M. The safety and tolerability of valproate sodium. Expert Opinion on Drug Safety. 2017. 5. Tomson T, et al. Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia. 2015. 6. American Epilepsy Society guidelines for valproate use 7. Clinical Pharmacokinetics of Valproate. Clinical Pharmacokinetics. 2018.
Note: This monograph provides general information. Always consult current prescribing information and clinical guidelines for specific patient care decisions.