What is the interaction between Lamictal (lamotrigine) and Depakote (valproate)?

Lamotrigine and Valproate Interaction: Clinical Implications

When lamotrigine is combined with valproate, valproate significantly inhibits lamotrigine metabolism, increasing lamotrigine levels by 165% and requiring substantial lamotrigine dose reduction to prevent toxicity. 1

Pharmacokinetic Interaction Mechanism

• Valproate inhibits the glucuronidation of lamotrigine, resulting in:

  • Increase in lamotrigine half-life from 26 to 70 hours (165% increase) 1
  • Decreased lamotrigine clearance 2
  • Higher lamotrigine serum concentrations at the same dose 1

• Bidirectional interaction also occurs:

  • Lamotrigine can decrease valproate concentrations by approximately 25% 2
  • Lamotrigine increases valproate oral clearance from 7.2 to 9.0 ml/hr/kg 2

Clinical Implications and Management

Dosing Adjustments

• When adding lamotrigine to valproate therapy:
  • Reduce lamotrigine starting dose to approximately 25% of standard dose 1
  • Use slower titration schedule (typically doubling the time between dose increases) 1
  • Target maintenance dose should be 50-75% lower than standard lamotrigine monotherapy dose 1

Adverse Effects Risk

• Serious skin reactions (Stevens-Johnson Syndrome, toxic epidermal necrolysis) can occur with concomitant use 1
• Risk of rash is not necessarily higher than with other combinations when appropriate dosing is used (13% incidence reported) 3
• Other potential adverse effects include:
  • Fatigue (12%)
  • Gastrointestinal symptoms (9%)
  • Dizziness, headache, and insomnia (3% each) 3

Monitoring Recommendations

• Monitor lamotrigine serum levels when:

  • Adding or removing valproate from lamotrigine therapy
  • Adjusting doses of either medication
  • Signs of toxicity appear (ataxia, dizziness, diplopia, headache)
  • Breakthrough seizures occur 4

• When discontinuing valproate in a patient on lamotrigine:

  • Complete reversal of the inhibitory effect takes 10-14 days 5
  • Lamotrigine dose may need to be increased gradually during this period
  • Close monitoring for breakthrough seizures is essential 5

Clinical Efficacy Considerations

• Despite the interaction challenges, the combination of lamotrigine and valproate can be effective for:
  • Refractory epilepsy 6
  • Bipolar disorder maintenance therapy 4
  • Treatment-resistant mood disorders 4

Practical Management Algorithm

1. Starting combination therapy:

   • If patient is on valproate and adding lamotrigine:

     • Begin with lamotrigine 25mg every other day for 2 weeks
     • Increase to 25mg daily for 2 weeks
     • Then increase by 25-50mg increments every 1-2 weeks as needed/tolerated

   • If patient is on lamotrigine and adding valproate:

     • Reduce lamotrigine dose by 50% immediately
     • Monitor levels and symptoms
     • Further adjust lamotrigine dose based on clinical response and levels

2. Discontinuing one agent:

   • If discontinuing valproate:

     • Plan to approximately double lamotrigine dose over 2-3 weeks
     • Monitor for breakthrough seizures or mood symptoms

   • If discontinuing lamotrigine:

     • Taper gradually to minimize withdrawal effects
     • No specific adjustment needed for valproate

3. Monitoring parameters:

   • Clinical efficacy (seizure control, mood stability)
   • Signs of lamotrigine toxicity (dizziness, diplopia, ataxia, headache)
   • Skin reactions (particularly during first 8 weeks)
   • Consider therapeutic drug monitoring when clinically indicated

Conclusion

The lamotrigine-valproate interaction is clinically significant and requires careful dose adjustments and monitoring. When properly managed, this combination can be safely used with an acceptable side effect profile and may provide therapeutic benefits for patients with epilepsy or bipolar disorder.