What are the potential drug interactions with Depakote (valproate) in a patient with a history of epilepsy, bipolar disorder, or migraine headaches?

Depakote (Valproate) Drug Interactions

Valproate interacts with numerous medications through multiple mechanisms including enzyme inhibition, protein binding displacement, and metabolic interference, requiring careful dose adjustments and monitoring when combined with other drugs.

Major Enzyme-Inducing Antiepileptic Drug Interactions

Carbamazepine, phenytoin, phenobarbital, and primidone significantly accelerate valproate metabolism, often requiring doubled valproate doses to maintain therapeutic levels, particularly in children. 1, 2, 3

• These enzyme-inducing antiepileptics markedly increase valproate clearance through metabolic induction 2, 3
• Rifampin increases valproate oral clearance by 40%, necessitating dose adjustment 1
• Dosage requirements may need to be doubled in response to enzyme induction effects 2

Valproate as a Metabolic Inhibitor

Phenobarbital Interaction

Valproate inhibits phenobarbital metabolism, increasing its half-life by 50% and decreasing clearance by 30%, often requiring phenobarbital dose reduction to prevent severe CNS depression and neurotoxicity. 1, 2, 3

• Phenobarbital concentrations can increase significantly (e.g., from 48 to 68 μg/mL), causing clinically significant neurotoxicity 4
• Monitor closely for severe CNS depression with or without significant elevations of barbiturate concentrations 1
• Primidone, which metabolizes to a barbiturate, likely has similar interactions 1

Phenytoin Interaction

Valproate displaces phenytoin from plasma protein binding sites and inhibits hepatic metabolism, increasing free phenytoin fraction by 60%, which can cause toxicity at concentrations normally considered therapeutic. 1, 2, 3

• The increased free fraction alters the relationship between total phenytoin concentration and pharmacologic effect 2
• Clinical toxicity may occur at concentrations usually in the therapeutic range 2
• Total phenytoin plasma concentration may decrease by 25% while free concentration increases 1

Carbamazepine Interaction

Valproate decreases carbamazepine serum levels by 17% but increases the active carbamazepine-10,11-epoxide metabolite by 45%, potentially causing toxicity despite lower parent drug levels. 1, 5, 2

• This interaction can lead to carbamazepine toxicity even when carbamazepine levels appear decreased 5
• Quetiapine further increases the carbamazepine epoxide to carbamazepine ratio, compounding toxicity risk 5

Lamotrigine Interaction

Valproate increases lamotrigine elimination half-life from 26 to 70 hours (165% increase), requiring lamotrigine dose reduction and increasing risk of serious skin reactions including Stevens-Johnson Syndrome and toxic epidermal necrolysis. 1

• This is a critical interaction requiring mandatory lamotrigine dose adjustment 1
• Refer to lamotrigine package insert for specific dosing guidelines with concomitant valproate 1

Tricyclic Antidepressant Interaction

Valproate decreases amitriptyline plasma clearance by 21% and nortriptyline net clearance by 34%, with rare postmarketing reports of toxicity requiring amitriptyline level monitoring and dose reduction. 1

Critical Life-Threatening Interactions

Carbapenem Antibiotics

Ertapenem, imipenem, and meropenem cause clinically significant reductions in valproic acid concentrations, resulting in loss of seizure control through an incompletely understood mechanism. 1

• Monitor valproic acid concentrations frequently after initiating carbapenem therapy 1
• Consider alternative antibacterial or anticonvulsant therapy if concentrations drop significantly or seizure control deteriorates 1

Topiramate-Associated Hyperammonemic Encephalopathy

Concomitant topiramate and valproate administration causes hyperammonemia with or without encephalopathy, presenting with acute alterations in consciousness, cognitive dysfunction, lethargy, vomiting, and potentially hypothermia. 1, 6

• This adverse event occurs in patients who tolerated either drug alone and is not due to pharmacokinetic interaction 1
• Symptoms typically abate with discontinuation of either drug 1
• Early recognition requires high index of suspicion in any patient on valproate presenting with impaired consciousness 6
• Check ammonia level in patients with unexplained lethargy, vomiting, or mental status changes 1

Aspirin Interaction

Aspirin inhibits valproate metabolism and displaces it from protein binding sites, increasing free valproate fraction by 4-fold and decreasing beta-oxidation by 83%. 1

• Exercise caution when co-administering valproate and aspirin 1

Antipsychotic Drug Interactions

Valproate decreases aripiprazole concentrations and has conflicting effects on clozapine (may increase or decrease levels), while chlorpromazine possibly increases valproate concentrations. 7, 5

• Carbamazepine decreases risperidone, olanzapine, clozapine, ziprasidone, haloperidol, and chlorpromazine concentrations when combined with antipsychotics 5
• Lamotrigine possibly increases clozapine concentrations 5
• Haloperidol administration (6-10 mg/day) does not significantly change valproate trough levels 1

Other Significant Interactions

Felbamate

Felbamate increases mean valproate peak concentration by 35% at 1200 mg/day and 51% at 2400 mg/day, requiring valproate dose reduction when initiating felbamate. 1

Ethosuximide

Valproate increases ethosuximide elimination half-life by 25% and decreases total clearance by 15%, requiring monitoring when used with other anticonvulsants. 1

Benzodiazepines

Valproate displaces diazepam from plasma albumin binding, increasing free diazepam fraction by 90% and reducing plasma clearance by 25%. 1

• Volume of distribution for free diazepam reduced by 20% 1
• Elimination half-life remains unchanged 1
• Concomitant valproic acid and clonazepam may induce absence status in patients with history of absence seizures 1

Monitoring Requirements

Monitor platelet counts and coagulation parameters before initiating therapy and periodically, as thrombocytopenia occurs in 27% of patients at approximately 50 mg/kg/day, with probability increasing significantly at total valproate concentrations ≤110 µg/mL (females) or ≥135 µg/mL (males). 1

• Check platelet count and coagulation parameters prior to planned surgery 1
• Evidence of hemorrhage, bruising, or coagulation disorder indicates need for dose reduction or withdrawal 1

Check ammonia levels in patients with unexplained lethargy, vomiting, changes in mental status, or hypothermia, as hyperammonemia can occur despite normal liver function tests. 1

• Discontinue valproate if ammonia is increased and initiate appropriate interventions 1
• Investigate for underlying urea cycle disorders 1
• Asymptomatic ammonia elevations require close monitoring and possible discontinuation if persistent 1

Clinically Unimportant Interactions

• Antacids (Maalox, Trisogel, Titralac) do not affect valproate absorption 1
• Cimetidine and ranitidine do not affect valproate clearance 1
• Chlorpromazine causes only 15% increase in valproate trough levels 1