Depakene - Drug Monograph

Introduction

Depakene (valproic acid) is an anticonvulsant medication primarily used for the management of various seizure disorders. First approved by the FDA in 1978, it belongs to the class of fatty acid derivatives and represents one of the broad-spectrum antiepileptic drugs available in clinical practice. Valproic acid is also marketed under various other brand names and is available in multiple formulations including capsules, syrup, and sprinkle formulations.

Mechanism of Action

Valproic acid demonstrates multiple mechanisms of action that contribute to its anticonvulsant properties:

• Enhances GABAergic neurotransmission by inhibiting GABA transaminase and succinic semialdehyde dehydrogenase
• Increases GABA availability by potentially stimulating glutamic acid decarboxylase activity
• Modulates voltage-sensitive sodium channels
• May exert effects on T-type calcium channels
• Demonstrates inhibitory effects on NMDA receptors

The exact contribution of each mechanism to its overall anticonvulsant effect remains incompletely understood, but the collective actions result in increased seizure threshold and reduced seizure spread.

Indications

• Monotherapy and adjunctive therapy for complex partial seizures
• Adjunctive therapy for simple and complex absence seizures
• Treatment of multiple seizure types including tonic-clonic seizures

• Migraine prophylaxis
• Bipolar disorder maintenance treatment
• Neuropathic pain management
• Agitation in dementia (with caution)

Dosage and Administration

• Initial dose: 10-15 mg/kg/day in divided doses
• Increase by 5-10 mg/kg/day at weekly intervals
• Maximum recommended dose: 60 mg/kg/day

• Initial dose: 10-15 mg/kg/day in divided doses
• Increase at weekly intervals by 5-10 mg/kg/day
• Maximum dose: 60 mg/kg/day

• Elderly: Start with lower doses due to reduced clearance
• Hepatic impairment: Contraindicated in significant liver disease
• Renal impairment: Dose adjustment may be necessary

• Administer with food to reduce gastrointestinal irritation
• Capsules should be swallowed whole
• Syrup formulation available for those unable to swallow capsules
• Do not administer with carbonated beverages (may cause rapid release)

Pharmacokinetics

• Rapid and nearly complete absorption
• Bioavailability: Approximately 100% for syrup, slightly lower for capsules
• Food delays absorption but does not affect total bioavailability
• Time to peak concentration: 1-4 hours

• Volume of distribution: 0.13-0.23 L/kg
• Protein binding: Concentration-dependent (85-95% at therapeutic levels)
• Crosses blood-brain barrier and placenta
• Secreted in breast milk

• Extensive hepatic metabolism via glucuronidation and mitochondrial β-oxidation
• Multiple cytochrome P450 enzymes involved (CYP2C9, CYP2A6, CYP2B6)
• Generates multiple active metabolites including 2-en-valproate and 3-keto-valproate

• Half-life: 9-16 hours in adults (shorter in children)
• Primarily renal excretion of metabolites (1-3% unchanged drug)
• Clearance: Age-dependent, higher in children

Contraindications

• Known hypersensitivity to valproic acid, valproate sodium, or any component of the formulation
• 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, highest risk in children under 2 years, those with mitochondrial 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 other hematologic abnormalities
• Hyperammonemia with or without encephalopathy
• Somnolence in elderly patients with dementia
• Suicidal behavior and ideation
• Multiorgan hypersensitivity reactions

Drug Interactions

• Other anticonvulsants: May alter levels of both drugs (particularly phenobarbital, phenytoin, lamotrigine)
• Aspirin: Increases free valproate concentrations
• Carbapenem antibiotics: Significantly reduce valproate levels
• Warfarin: May potentiate anticoagulant effect
• Benzodiazepines: Increased CNS depression
• Zidovudine: Increased risk of hematologic toxicity

• Drugs highly protein-bound may displace valproate (phenytoin, aspirin)
• Monitoring free valproate levels recommended when adding/discontinuing protein-bound drugs

Adverse Effects

• Nausea, vomiting, diarrhea
• Drowsiness, dizziness
• Tremor
• Weight gain
• Alopecia

• Hepatotoxicity
• Pancreatitis
• Thrombocytopenia
• Hyperammonemic encephalopathy
• Stevens-Johnson syndrome
• Cognitive impairment
• Polycystic ovarian syndrome

Monitoring Parameters

• Complete blood count with platelets
• Liver function tests
• Ammonia level
• Pregnancy test in women of childbearing potential
• Comprehensive metabolic panel

• Valproate levels: Therapeutic range 50-100 mcg/mL
• CBC with platelets every 3-6 months
• LFTs every 3-6 months
• Ammonia level if symptoms suggest encephalopathy
• Weight and BMI regularly
• Monitoring for signs of pancreatitis

• More frequent monitoring in children, elderly, and those with comorbidities
• Free valproate levels in patients with hypoalbuminemia or renal failure

Patient Education

• Take medication exactly as prescribed, with food if gastrointestinal upset occurs
• Do not abruptly discontinue medication (risk of seizure recurrence)
• Use effective contraception during treatment
• Report immediately: jaundice, abdominal pain, nausea/vomiting, unusual bleeding/bruising
• Regular blood tests are necessary for safety monitoring
• Avoid alcohol consumption during therapy
• Be aware of potential cognitive effects when driving or operating machinery
• Inform all healthcare providers about valproate therapy
• Carry medical identification indicating anticonvulsant therapy

References

1. FDA Prescribing Information: Depakene (valproic acid) capsules 2. Johannessen CU, Johannessen SI. Valproate: past, present, and future. CNS Drug Rev. 2003;9(2):199-216. 3. Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs. 2002;16(10):695-714. 4. Nanau RM, Neuman MG. Adverse drug reactions induced by valproic acid. Clin Biochem. 2013;46(15):1323-1338. 5. Tomson T, Marson A, Boon P, et al. Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia. 2015;56(7):1006-1019. 6. American Epilepsy Society guidelines for antiepileptic drug monitoring. Epilepsy Currents. 2018;18(4):258-266. 7. Clinical Pharmacokinetics of Valproate: A Systematic Review. Clin Pharmacokinet. 2021;60(10):1233-1248.