UDP-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-metabolising enzymes, and interactions between lamotrigine and drugs metabolised 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.
Effects of Other Drugs on Glucuronidation of Lamotrigine: Drugs That Significantly Inhibit Glucuronidation of Lamotrigine: Valproate.
Drugs That Significantly Induce Glucuronidation of Lamotrigine: Carbamazepine, phenytoin, primidone, phenobarbitone, rifampicin, ethinyloestradiol/levonorgestrel combination**.
Drugs That Do Not Significantly Inhibit or Induce Glucuronidation of Lamotrigine: Lithium, bupropion, olanzapine, oxcarbazepine.
**Other oral contraceptive and HRT treatments have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.
Interactions Involving AEDs (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 (see Precautions and Dosage & Administration).
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. Other drug classes which induce hepatic drug-metabolising enzymes may also 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 Apo-Lamotrigine. 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.
Although changes in the plasma concentrations of other AEDs have been reported, controlled studies have shown no evidence that lamotrigine affects the plasma concentrations of concomitant AEDs. Evidence from in vitro studies indicates that lamotrigine does not displace other AEDs from protein-binding sites.
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. The pharmacokinetic interaction between lamotrigine and oxcarbazepine in children has not been studied.
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 Apo-Lamotrigine 100 mg/day.
Multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of Apo-Lamotrigine 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.
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, 30 mcg ethinyl oestradiol/150 mcg levonorgestrel 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.
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/day 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 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).