GIROTEC Tablet Ref.[51195] Active ingredients: Lamotrigine

Lamotrigine is well and completely absorbed from the gut. The absorption is unaffected by food. The time to peak concentration is 1,4 to 4,8 hours. The mean elimination half-life is 25 10 hours and the pharmacokinetic profile is linear up to 450 mg, the highest single dose tested. The half-life of lamotrigine is affected by concomitant use of enzyme-inducing medicines such as phenytoin, carbamazepine, phenobarbital or primidone with a mean value of approximately 14 hours.

The half-life of lamotrigine increases to approximately 59 hours when co-administered with valproic acid alone (see “Interactions” and “Dosage and Directions for Use”).

Following multiple dose administration of lamotrigine (150 mg twice daily) there is modest induction of its own metabolism, resulting in a 25% decrease in the elimination half-life at steady state. Lamotrigine is moderately (55%) bound to plasma proteins.

Hepatic metabolism followed by renal excretion is the principal route of elimination of lamotrigine.

Clearance adjusted for bodyweight is higher in children aged 12 years and under than in adults, with the highest values in children less than 5 years. The half-life of lamotrigine is generally shorter in children than in adults with a mean value of approximately 7 hours when given with enzyme- inducing medicines such as carbamazepine and phenytoin.

Special populations

Elderly

Results of a population pharmacokinetic analysis including both young and elderly patients with epilepsy, enrolled in the same trials, indicated that the clearance of lamotrigine did not change to a clinical relevant extent. After single doses, apparent clearance decreased by 12% from 35 ml/min at age 20 to 31 ml/min at 70 years. The decrease after 48 weeks of treatment was 10% from 41 to 37 ml/min between the young and elderly groups. In addition, pharmacokinetics of lamotrigine was studied in 12 healthy elderly subjects following a 150 mg single dose. The mean clearance in the elderly (0,39 ml/min/kg) lies within the range of the mean clearance values (0,31 to 0,65 ml/min/kg) obtained in 9 studies with non-elderly adults after single dose of 30 to 450 mg.

Patients with renal impairment

Twelve volunteers with chronic renal failure, and another 6 individuals undergoing haemodialysis were given a single 100 mg dose of lamotrigine. Mean CL/F were 0, 42 ml/min/kg (between haemodialysis) and 1,57 ml/min/kg (during haemodialysis) compared to 0,58 ml/min/kg in healthy volunteers. Mean plasma half-lives were 42,9 hours (chronic renal failure) 57,4 hours (between haemodialysis) and 13, 0 hours (during haemodialysis), compared to 26, 2 hours in healthy volunteers. On average, approximately 20% (range = 5, 8 to 35, 1) of the amount of lamotrigine present in the body was eliminated during a 4 hour haemodialysis session. For this patient population, initial dose of lamotrigine should be based in patients antiepileptic drug (AED) regimen; reduced maintenance doses should be used in patients with significant renal functional impairment (see “ Dosage and Directions For Use”).

Patients with hepatic impairment

A single-dose pharmacokinetic study was performed in 24 subjects with various degrees of hepatic impairment and 12 healthy subjects as control. The median apparent clearance of lamotrigine was 0,31, 0,24 and 0,10 ml/min/kg in patients with grade A, B or C (Child-Plough Classification) Hepatic impairment, respectively, compared to 0,34 ml/min/kg in healthy controls. Reduced doses should be used in patients with grade B or C hepatic impairment (see “Dosage and Directions For Use”).