Drug Interactions with Lamotrigine (Lamictal)
Direct Answer
Among the medications you listed, only valproate (if you meant Depakote rather than Plaquenil) significantly affects lamotrigine levels—it approximately doubles them by inhibiting lamotrigine metabolism. Plaquenil (hydroxychloroquine), gabapentin, duloxetine, and sertraline do not have clinically significant effects on lamotrigine blood levels.
Detailed Interaction Profile
Medications That DO NOT Affect Lamotrigine Levels
Hydroxychloroquine (Plaquenil): No documented pharmacokinetic interaction with lamotrigine exists in the medical literature. These medications can be safely co-administered without dose adjustment of lamotrigine.
Gabapentin: Does not interact with lamotrigine metabolism. Gabapentin is renally eliminated and does not affect the glucuronidation pathways responsible for lamotrigine clearance 1.
Duloxetine: No clinically significant interaction with lamotrigine has been reported. Duloxetine is metabolized primarily by CYP1A2 and CYP2D6, not by the UGT enzymes that metabolize lamotrigine 1.
Sertraline: Does not significantly affect lamotrigine levels. Sertraline has minimal effect on CYP450 enzymes and does not inhibit the UGT1A4 or UGT2B10 enzymes responsible for lamotrigine glucuronidation 1.
Critical Interaction to Know: Valproate
If you were asking about valproate (Depakote) rather than Plaquenil, this is the most clinically important interaction:
Valproate dramatically increases lamotrigine levels by inhibiting UGT-mediated glucuronidation, increasing lamotrigine half-life from approximately 24-37 hours to 48-59 hours 2. This interaction occurs because valproate inhibits both UGT1A4 and UGT2B10, the two major enzymes responsible for lamotrigine metabolism 3, 4.
When valproate is co-administered with lamotrigine, the lamotrigine dose must be reduced by approximately 50% to maintain therapeutic levels and avoid toxicity 2. Conversely, if valproate is discontinued in a patient taking both medications, lamotrigine levels will drop significantly, potentially leading to breakthrough seizures or mood destabilization.
Lamotrigine Metabolism Pathway
Lamotrigine is primarily metabolized (approximately 90% of the dose) by UDP-glucuronosyltransferases (UGT), specifically UGT1A4 (contributing 42-64% of metabolism) and UGT2B10 (contributing 32-57% of metabolism) 3, 4. This glucuronidation produces lamotrigine N2-glucuronide, which is then renally excreted 2, 4.
Because lamotrigine metabolism does not involve cytochrome P450 enzymes significantly, most psychiatric medications that affect CYP enzymes (including SSRIs like sertraline and SNRIs like duloxetine) do not alter lamotrigine levels 2.
Medications That DO Affect Lamotrigine Levels
For completeness, you should be aware of these interactions:
- Enzyme-inducing anticonvulsants (phenytoin, carbamazepine, phenobarbital) reduce lamotrigine half-life to 13.5-15 hours, requiring higher lamotrigine doses 2
- Valproate increases lamotrigine half-life to 48-59 hours, requiring lower lamotrigine doses 2
- Oral contraceptives containing ethinyl estradiol can reduce lamotrigine levels by approximately 50% 2
Clinical Monitoring Recommendations
When combining lamotrigine with any of the medications you mentioned (hydroxychloroquine, gabapentin, duloxetine, or sertraline), no lamotrigine dose adjustment is required 2. However, if the patient is also taking valproate, remember that lamotrigine dosing must be reduced by approximately 50% 2.
Therapeutic lamotrigine levels are not firmly established, but a putative therapeutic range of 1-4 mg/L has been proposed, though some patients benefit from levels exceeding 10 mg/L without toxicity 2. Routine therapeutic drug monitoring of lamotrigine is not typically necessary unless there are concerns about adherence, toxicity, or drug interactions 2, 5.
Common Pitfall to Avoid
The most dangerous error is failing to reduce lamotrigine dose when adding valproate, or failing to increase lamotrigine dose when discontinuing valproate 2. This can lead to either lamotrigine toxicity (with valproate addition) or loss of therapeutic effect (with valproate discontinuation). Neither scenario applies to the medications you asked about (Plaquenil, gabapentin, duloxetine, sertraline), which can all be safely combined with lamotrigine without dose adjustment.