What are the major interactions between valproate and lamotrigine?

From the Guidelines

Valproate significantly increases lamotrigine blood levels by inhibiting lamotrigine's metabolism, creating a potentially dangerous interaction that requires careful management. When these medications are used together, lamotrigine doses typically need to be reduced by approximately 50% compared to standard dosing. This interaction occurs because valproate inhibits glucuronidation, the primary pathway for lamotrigine metabolism, resulting in a near doubling of lamotrigine's half-life from about 24 hours to 48-70 hours. The combination increases the risk of serious adverse effects, particularly skin rashes including Stevens-Johnson syndrome and toxic epidermal necrolysis. Some key points to consider when using valproate and lamotrigine together include:

• Starting lamotrigine at a lower dose (typically 25mg every other day for two weeks) with a slower titration schedule (increasing by 25-50mg every 1-2 weeks)
• Regular monitoring of lamotrigine levels is recommended, especially after dosage adjustments or if toxicity is suspected
• Patients should be educated about signs of toxicity including dizziness, diplopia, ataxia, headache, nausea, and particularly any skin reactions, which warrant immediate medical attention. Although the provided study 1 does not directly address the interaction between valproate and lamotrigine, the known pharmacokinetic interaction between these two medications is well established in clinical practice.

From the FDA Drug Label

In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase) The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration.

The major interactions between valproate and lamotrigine are:

• Increased elimination half-life of lamotrigine: Valproate co-administration increases the elimination half-life of lamotrigine by 165%.
• Dose reduction of lamotrigine: The dose of lamotrigine should be reduced when co-administered with valproate.
• Risk of serious skin reactions: Concomitant administration of lamotrigine and valproate may increase the risk of serious skin reactions, such as Stevens-Johnson Syndrome and toxic epidermal necrolysis 2.

From the Research

Major Interactions between Valproate and Lamotrigine

• The concomitant use of valproate and lamotrigine has been shown to increase the half-life of lamotrigine and decrease its clearance, without substantially altering its linear kinetics 3.
• The addition of lamotrigine to valproate therapy has been associated with a small but significant decrease in steady-state valproate plasma concentration, and an increase in oral clearance of valproate 3.
• The formation clearance of hepatotoxic valproate metabolites, such as 2-n-propyl-4-pentenoic acid and 2-propyl-2,4-pentadienoic acid, is unaffected by lamotrigine administration 3.
• The interaction between lamotrigine and valproate may affect the efficacy and toxicity of both drugs, and dosage adjustments may be necessary when they are used together 4.
• In pediatric patients with refractory epilepsy, the co-administration of lamotrigine and valproate has been shown to be effective in reducing seizure frequency, with a response rate of 64.3% 5.
• In adults with newly diagnosed epilepsy, lamotrigine and valproate have been shown to have similar efficacy, but lamotrigine may be better tolerated 6.
• The combination of sodium valproate and lamotrigine has been shown to improve quality of life and reduce serum inflammatory factors in patients with poststroke secondary epilepsy 7.

Clinical Implications

• The use of valproate and lamotrigine together requires careful monitoring of plasma concentrations and dosage adjustments to minimize the risk of adverse effects 3, 4.
• The combination of lamotrigine and valproate may be effective in reducing seizure frequency in patients with refractory epilepsy, but it requires careful monitoring of adverse effects 5.
• In patients with newly diagnosed epilepsy, lamotrigine may be a better option than valproate due to its better tolerability profile 6.
• The use of sodium valproate and lamotrigine together may be beneficial in patients with poststroke secondary epilepsy, with improvements in quality of life and reductions in serum inflammatory factors 7.