Uridine diphosphate-glucuronyl transferases have been identified as the enzymes responsible for metabolism of lamotrigine. There is no evidence that lamotrigine causes clinically significant induction or inhibition of hepatic oxidative drug-metabolizing enzymes, and interactions between lamotrigine and drugs metabolized by cytochrome P-450 enzymes are unlikely to occur. Lamotrigine may induce its own metabolism but the effect is modest and unlikely to have significant clinical consequences. (See Table 6.)
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Interactions Involving Anti-Epileptic Drugs (see Dosage & Administration): Valproate, which inhibits the glucuronidation of lamotrigine, reduces the metabolism of lamotrigine and increases the mean half-life of lamotrigine nearly 2-fold.
Certain antiepileptic agents (eg, phenytoin, carbamazepine, phenobarbitone and primidone) which induce hepatic drug-metabolising enzymes induce the metabolism glucuronidation of lamotrigine and enhance the metabolism of lamotrigine.
There have been reports of central nervous system events including dizziness, ataxia, diplopia, blurred vision and nausea in patients taking carbamazepine following the introduction of Lamictal. These events usually resolve when the dose of carbamazepine is reduced. A similar effect was seen during a study of lamotrigine and oxcarbazepine in healthy adult volunteers, but dose reduction was not investigated.
In a study in healthy adult volunteers using doses of lamotrigine 200 mg and oxcarbazepine 1200 mg, oxcarbazepine did not alter the metabolism of lamotrigine and lamotrigine did not alter the metabolism of oxcarbazepine.
In a study of healthy volunteers, co-administration of felbamate (1200 mg twice daily) with Lamictal (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.
Based on a retrospective analysis of plasma levels in patients who received Lamictal both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.
Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.
Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.
Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of Lamictal resulted in a 15% increase in topiramate concentrations.
In a study of patients with epilepsy, co-administration of zonisamide (200-400 mg daily) with Lamictal (150-500 mg daily) for 35 days had no significant effect on the pharmacokinetics of lamotrigine.
Although changes in the plasma concentrations of other antiepileptic drugs have been reported, controlled studies have shown no evidence that lamotrigine affects the plasma concentrations of concomitant antiepileptic drugs. Evidence from in vitro studies indicates that lamotrigine does not displace other antiepileptic drugs from protein binding sites.
Interactions Involving Other Psychoactive Agents (see Dosage & Administration): The pharmacokinetics of lithium after 2 g of anhydrous lithium gluconate given twice daily for 6 days to 20 healthy subjects were not altered by co-administration of Lamictal 100 mg daily.
Multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of Lamictal in 12 subjects and had only a slight increase in the AUC of lamotrigine glucuronide.
In a study in healthy adult volunteers, olanzapine 15 mg reduced the AUC and Cmax of lamotrigine by an average of 24% and 20%, respectively. An effect of this magnitude is not generally expected to be clinically relevant. Lamotrigine at 200 mg did not affect the pharmacokinetics of olanzapine.
Multiple oral doses of Lamictal 400 mg daily had no clinically significant effect on the single dose pharmacokinetics of risperidone 2 mg in 14 healthy adult volunteers. Following the co-administration of risperidone 2 mg with lamotrigine, 12 out of the 14 volunteers reported somnolence compared to 1 out of 20 when risperidone was given alone, and none when Lamictal was administered alone.
In vitro inhibition experiments indicated that the formation of lamotrigine's primary metabolite, the 2-N-glucuronide, was minimally affected by co-incubation with amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol, or lorazepam. Bufuralol metabolism data from human liver microsome suggested that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6. Results of in vitro experiments also suggest that clearance of lamotrigine is unlikely to be affected by clozapine, phenelzine, risperidone, sertraline or trazodone.
Interactions Involving Hormonal Contraceptives: Effect of Hormonal Contraceptives on Lamotrigine Pharmacokinetics: In a study of 16 female volunteers, ethinyloestradiol 30 mcg/levonorgestrel 150 mcg in a combined oral contraceptive pill caused an approximately 2-fold increase in lamotrigine oral clearance, resulting in an average 52% and 39% reduction in lamotrigine AUC and Cmax, respectively. Serum lamotrigine concentrations gradually increased during the course of the week of inactive medication (eg, "pill-free" week), with pre-dose concentrations at the end of the week of inactive medication being, on average, approximately 2-fold higher than during co-therapy (see Dosage & Administration, and Precautions).
Effect of Lamotrigine on Hormonal Contraceptive Pharmacokinetics: In a study of 16 female volunteers, a steady state dose of lamotrigine 300 mg had no effect on the pharmacokinetics of the ethinyloestradiol component of a combined oral contraceptive pill. A modest increase in oral clearance of the levonorgestrel component was observed, resulting in an average 19% and 12% reduction in levonorgestrel AUC and Cmax, respectively. Measurement of serum FSH, LH and oestradiol during the study indicated some loss of suppression of ovarian hormonal activity in some women, although measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 subjects. The impact of the modest increase in levonorgestrel clearance, and the changes in serum FSH and LH, on ovarian ovulatory activity is unknown (see Precautions). The effects of doses of lamotrigine other than 300 mg daily have not been studied and studies with other female hormonal preparations have not been conducted.
Interactions Involving Other Medications: In a study in 10 male volunteers, rifampicin increased lamotrigine clearance and decreased lamotrigine half-life (t½) due to induction of the hepatic enzymes responsible for glucuronidation. In patients receiving concomitant therapy with rifampicin, the treatment regimen recommended for lamotrigine and concurrent glucuronidation inducers should be used (see Dosage & Administration).
In a study in healthy volunteers, lopinavir/ritonavir approximately halved the plasma concentrations of lamotrigine, probably by induction of glucuronidation. In patients receiving concomitant therapy with lopinavir/ritonavir, the treatment regimen recommended for lamotrigine and concurrent glucuronidation inducers should be used (see Dosage & Administration).
In a study in healthy adult volunteers, atazanavir/ritonavir (300 mg/100 mg) reduced the plasma AUC and Cmax of lamotrigine (single 100 mg dose) by an average of 32% and 6%, respectively (see Dosage and Administration - General Dosing Recommendations for LAMICTAL in Special Patient Populations).
Data from in vitro assessment of the effect of lamotrigine at OCT 2 demonstrate that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of OCT 2 at potentially clinically relevant concentrations. These data demonstrate that lamotrigine is a more potent inhibitor of OCT 2 than cimetidine, with IC50 values of 53.8 micromolar and 186 micromolar, respectively (see Precautions).
Interactions Involving Laboratory Tests: Lamictal has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false positive readings, particularly for phencyclidine (PCP). A more specific alternative chemical method should be used to confirm a positive result.
Incompatabilities: None reported.