Divalproex sodium - Drug Monograph

Introduction

Divalproex sodium is an anticonvulsant and mood-stabilizing medication that is a stable coordination compound comprised of sodium valproate and valproic acid in a 1:1 molar ratio. It is a prodrug that dissociates to valproate ions in the gastrointestinal tract. First approved by the FDA in 1983, divalproex sodium has become a cornerstone therapy for various neurological and psychiatric conditions, particularly epilepsy and bipolar disorder.

Mechanism of Action

Divalproex sodium exerts its therapeutic effects through multiple mechanisms:

• Enhances GABAergic neurotransmission by inhibiting GABA transaminase and succinic semialdehyde dehydrogenase
• Increases GABA availability by stimulating glutamic acid decarboxylase activity
• Modulates voltage-gated sodium channels, reducing neuronal excitability
• May affect T-type calcium channels and NMDA receptor-mediated excitation
• Exhibits histone deacetylase inhibition, which may contribute to its mood-stabilizing effects

Indications

FDA-approved indications:

• Monotherapy and adjunctive therapy for complex partial seizures, simple and complex absence seizures, and multiple seizure types including absence
• Treatment of manic episodes associated with bipolar disorder
• Prophylaxis of migraine headaches

Off-label uses (with varying evidence):

• Neuropathic pain syndromes
• Agitation in dementia
• Impulse control disorders

Dosage and Administration

• Adults and children >10 years: Initial 10-15 mg/kg/day, increase by 5-10 mg/kg/week
• Maximum recommended dose: 60 mg/kg/day

• Initial: 750 mg/day in divided doses
• Target: 20-30 mg/kg/day, not to exceed 60 mg/kg/day

• Initial: 250 mg twice daily
• Maximum: 1000 mg/day

• Geriatric: Start with lowest effective dose, monitor closely
• Renal impairment: Dose reduction recommended for CrCl <10 mL/min
• Hepatic impairment: Contraindicated in significant hepatic dysfunction
• Pediatrics: Dosing based on weight, monitor closely for hepatotoxicity

• Available as delayed-release tablets, extended-release tablets, and sprinkle capsules
• Should be swallowed whole; do not crush or chew
• Administer with food to reduce GI irritation
• Dosing frequency: 2-4 times daily depending on formulation

Pharmacokinetics

• Bioavailability: >80% for divalproex sodium
• Tmax: 3-5 hours for delayed-release, 7-14 hours for extended-release
• Food may delay but not reduce absorption

• Volume of distribution: 0.13-0.23 L/kg
• Protein binding: 80-90%, concentration-dependent
• Crosses blood-brain barrier and placenta

• Extensive hepatic metabolism via glucuronidation, β-oxidation, and cytochrome P450
• Multiple metabolites, some pharmacologically active

• Half-life: 9-16 hours (adults), 7-13 hours (children)
• Clearance: 0.5-1.0 L/hr/1.73m²
• Primarily renal excretion (30-50% as glucuronide conjugates)

Contraindications

• Known hypersensitivity to valproate products
• Hepatic disease or significant hepatic dysfunction
• Known urea cycle disorders
• Mitochondrial disorders caused by POLG mutations
• Pregnancy for migraine prophylaxis
• Concomitant use with other hepatotoxic drugs in high-risk populations

Warnings and Precautions

1. Hepatotoxicity: Fatal hepatic failure reported, especially in children under 2 years, those with metabolic disorders, and those on multiple anticonvulsants 2. Teratogenicity: Neural tube defects and other major malformations reported 3. Pancreatitis: Life-threatening cases reported, both initially and after years of use

• Thrombocytopenia and impaired coagulation
• Hyperammonemic encephalopathy
• Somnolence in elderly patients
• Suicidal ideation and behavior
• Multiorgan hypersensitivity reactions
• Weight gain and metabolic effects

Drug Interactions

• Lamotrigine: ↑ lamotrigine levels, ↑ risk of serious rash
• Phenobarbital, phenytoin: ↓ valproate levels, variable effects on other drugs
• Carbamazepine: ↓ valproate levels, possible ↑ carbamazepine toxicity
• Warfarin: Altered anticoagulant effect (monitor INR closely)
• Aspirin: ↑ valproate free fraction, potential toxicity
• Benzodiazepines: Enhanced CNS depression
• Zidovudine: ↓ zidovudine clearance
• Topiramate: ↑ risk of hyperammonemia and encephalopathy
• Ethanol: Enhanced CNS depression

Adverse Effects

• Nausea/vomiting (15-30%)
• Somnolence/sedation (15-30%)
• Dizziness (10-20%)
• Tremor (10-20%)
• Weight gain (10-20%)
• Alopecia (5-15%)
• Diarrhea (5-15%)

• Hepatotoxicity (0.01-0.2%)
• Pancreatitis (0.005-0.1%)
• Thrombocytopenia (5-30%, dose-dependent)
• Hyperammonemic encephalopathy
• Stevens-Johnson syndrome
• Agranulocytosis
• Suicidal ideation and behavior

Monitoring Parameters

• Complete blood count with platelets
• Liver function tests (AST, ALT, bilirubin)
• Serum ammonia level
• Pregnancy test in women of childbearing potential
• Coagulation parameters if high risk

• LFTs every 2-4 weeks initially, then every 3-6 months
• CBC with platelets every 3-6 months
• Serum valproate levels (therapeutic range: 50-125 μg/mL)
• Ammonia levels if symptoms suggest encephalopathy
• Weight and metabolic parameters regularly
• Mood assessment in bipolar patients

• Target range: 50-125 μg/mL for most indications
• Draw trough levels before morning dose
• Free levels may be useful in special populations

Patient Education

• Take medication exactly as prescribed; do not stop abruptly
• Report any signs of liver problems: nausea, vomiting, abdominal pain, jaundice
• Report signs of pancreatitis: severe abdominal pain, nausea, vomiting
• Use effective contraception; discuss pregnancy planning with provider
• Avoid alcohol and other CNS depressants
• Be aware of potential drowsiness; use caution when driving or operating machinery
• Report unusual bleeding or bruising
• Regular blood tests are necessary for safety monitoring
• Notify all healthcare providers about valproate use before procedures
• Store medication properly and keep out of reach of children

• Women of childbearing potential: Discuss pregnancy prevention and risks
• Elderly: Increased risk of somnolence, falls, and tremor
• Pediatrics: Increased monitoring for hepatotoxicity required

References

1. FDA Prescribing Information: Depakote (divalproex sodium) 2. Johannessen CU, Johannessen SI. Valproate: past, present, and future. CNS Drug Rev. 2003;9(2):199-216. 3. Löscher W. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs. 2002;16(10):669-694. 4. Bowden CL. Valproate. Bipolar Disord. 2003;5(3):189-202. 5. Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239-1276. 6. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Bipolar Disorder. 2010. 7. Harden CL, Pennell PB, Koppel BS, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review). Neurology. 2009;73(2):142-149. 8. 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. 2006;47(7):1094-1120.