What are the major drug-to-drug interactions with valproate (valproic acid)?

From the Guidelines

Valproate has several major drug interactions that can affect its efficacy and safety, particularly with other anticonvulsants, CNS depressants, anticoagulants, and certain antibiotics, which can lead to decreased valproate levels, increased risk of bleeding, enhanced sedative effects, and increased toxicity of other medications 1.

Major Interactions

• Other anticonvulsants like phenytoin, carbamazepine, and phenobarbital can decrease valproate levels while valproate may increase their concentrations.
• Combining valproate with other CNS depressants such as benzodiazepines or alcohol can enhance sedative effects.
• Valproate can increase the risk of bleeding when used with anticoagulants like warfarin.
• It may also increase the toxicity of certain antibiotics like carbapenems by reducing valproate levels by up to 60-100%.
• Aspirin and other salicylates can displace valproate from protein binding sites, increasing free valproate levels.
• When combined with lamotrigine, valproate inhibits lamotrigine metabolism, potentially doubling its half-life and requiring lamotrigine dose reductions to prevent toxicity.
• Valproate may also increase ammonia levels when used with topiramate.

Mechanism of Interactions

These interactions occur because valproate is highly protein-bound and affects liver enzymes involved in drug metabolism.

Clinical Implications

Regular monitoring of drug levels, liver function, and clinical response is essential when valproate is used with these medications.

Specific Considerations

• Colesevelam, a bile acid sequestrant, does not appear to interact with valproic acid, but may interact with other medications such as warfarin and phenytoin 1.
• The potential for drug interactions with valproate necessitates a review of concurrent medications to minimize the risk of reduced absorption of concomitant medications 1.

From the Research

Major Drug Interactions with Valproate

The following are some major drug interactions with valproate:

• Valproate derivatives can interact with carbapenem antibiotics, such as meropenem, ertapenem, imipenem, and doripenem, leading to a decrease in valproate serum concentration and potentially causing seizures 2
• Valproic acid can interact with other anticonvulsants, such as phenobarbitone, primidone, and phenytoin, resulting in reciprocal interactions that may have important therapeutic consequences 3
• Valproate can interact with antipsychotic drugs, such as risperidone, olanzapine, quetiapine, clozapine, and haloperidol, with effects that depend on the induction or inhibition of cytochrome P450 isoenzymes and other mechanisms 4
• Lamotrigine and valproate can interact bidirectionally, with valproate increasing the half-life of lamotrigine and decreasing its clearance, and lamotrigine decreasing the steady-state valproate plasma concentration 5
• Valproate can interact with other drugs, such as carbamazepine, phenobarbital, primidone, and phenytoin, resulting in clinically significant pharmacologic interactions that may require dosage adjustments 6

Mechanisms of Interaction

The mechanisms of interaction between valproate and other drugs include:

• Enzyme induction, which can accelerate the metabolic conversion of valproate 3, 6
• Enzyme inhibition, which can decrease the metabolism of other drugs 3, 6
• Protein binding displacement, which can alter the relationship between total drug concentration and pharmacologic effect 3, 6
• Other mechanisms, such as the induction or inhibition of uridine diphosphate glucuronosyltransferase isoenzymes 4