The pharmacokinetics of LAMICTAL were not changed by coadministration of bupropion (see PRECAUTIONS: DRUG INTERACTIONS).

Coadministration of olanzapine did not have a clinically relevant effect on LAMICTAL pharmacokinetics (see PRECAUTIONS: DRUG INTERACTIONS).

Enzyme Induction

The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated.

Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a 37% increase in Cl/F at steady state compared to values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by LAMICTAL may not occur when LAMICTAL is given as adjunctive therapy in patients receiving carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.

Dose Proportionality

In healthy volunteers not receiving any other medications and given single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were maintained on other AEDs, there also was a linear relationship between dose and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg twice daily.

Elimination

(see Table 1).

Special Populations

Patients With Renal Insufficiency

Twelve volunteers with chronic renal failure (mean creatinine clearance = 13 mL/min; range = 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of LAMICTAL. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session.

Hepatic Disease

The pharmacokinetics of lamotrigine following a single 100-mg dose of LAMICTAL were evaluated in 24 subjects with mild, moderate, and severe hepatic dysfunction (Child-Pugh Classification system) and compared with 12 subjects without hepatic impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearance of lamotrigine in patients with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment was 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared to 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-life of lamotrigine in patients with mild, moderate, severe without ascites, and severe with ascites liver impairment was 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared to 33 ± 7 hours in healthy controls (for dosing guidelines, see DOSAGE AND ADMINISTRATION: Patient With Hepatic Impairment).

Age

Pediatric Patients

The pharmacokinetics of LAMICTAL following a single 2-mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients aged 10 months to 5.9 years and n = 26 for patients aged 5 to 11 years). Forty-three patients received concomitant therapy with other AEDs and 12 patients received LAMICTAL as monotherapy. Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 2.

Population pharmacokinetic analyses involving patients aged 2 to 18 years demonstrated that lamotrigine clearance was influenced predominantly by total body weight and concurrent AED therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects weighing less than 30 kg, compared with those weighing greater than 30 kg. Accordingly, patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses, based on clinical response, as compared with subjects weighing more than 30 kg being administered the same AEDs (see DOSAGE AND ADMINISTRATION). These analyses also revealed that, after accounting for body weight, lamotrigine clearance was not significantly influenced by age. Thus, the same weight-adjusted doses should be administered to children irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in adults were found to have similar effects in children.

Table 2. Mean Pharmacokinetic Parameters in Pediatric Patients With Epilepsy

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