Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: CIPLA MEDPRO (PTY) LTD., Building 9, Parc du Cap, Mispel Street, Bellville, 7530, Customer care number: 080 222 6662
Pharmacological classification: A.2.5 Anticonvulsants including antiepileptics
Pharmacotherapeutic group: Antiepileptics, Other antiepileptics
ATC code: N03AX09
In vitro studies show that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations. It inhibits human cardiac sodium channels with rapid onset and offset kinetics and strong voltage dependence, consistent with other Class IB antiarrhythmic agents. At therapeutic doses, lamotrigine did not slow ventricular conduction (widen QRS) in healthy individuals in a thorough QT study; however, in patients with clinically important structural or functional heart disease lamotrigine could potentially slow ventricular conduction (widen QRS) and induce proarrhythmia.
In vitro pharmacological studies suggest that lamotrigine blocks voltage-sensitive sodium channels, thereby stabilising neuronal membranes and inhibiting the presynaptic release of neurotransmitters, principally glutamate. Glutamate, an excitatory amino acid, is thought to play a key role in the generation of epileptic seizures.
In healthy fasting young adult volunteers, lamotrigine is completely absorbed from the gut. The peak plasma concentration occurs 2,5 hours after oral administration. The mean elimination half-life is 29 hours, and the pharmacokinetic profile is linear up to 450 mg, the highest single dose tested. The half-life of lamotrigine is decreased by concomitant medicine with a mean value of approximately 14 hours when given with enzyme-inducing medicines such as carbamazepine and phenytoin and increased to a mean of approximately 70 hours when co-administered with sodium valproate alone (see section 4.2). Following multiple administrations of lamotrigine (150 mg twice daily) to normal volunteers, there is modest induction of its own metabolism, resulting in a 25 % decrease in the elimination half-life at steady state. Lamotrigine is 55 % bound to plasma proteins. Clearance adjusted for bodyweight is higher in children aged 12 years and under than in adults, with the highest values in children under 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. The half-life of lamotrigine increases to mean values of approximately 45 to 55 hours when co-administered with sodium valproate alone (see section 4.2).
Clearance of lamotrigine does not differ to a clinically relevant extent between young and elderly patients.
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 doses of 30 to 450 mg.
12 volunteers with chronic renal failure and another 6 individuals undergoing hemodialysis were each given a single 100 mg dose of lamotrigine. Mean CL/F were 0,42 mL/min/kg (chronic renal failure), 0,33 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 = 5,6 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 doses of lamotrigine should be based on patients' anti-epileptic medicine (AEM) regimen; reduced maintenance doses should be used in patients with significant renal functional impairment (see section 4.2). Clearance and half-life of lamotrigine is reduced and prolonged, respectively, in patients with functional renal impairment. While initial doses of lamotrigine should be based on the patient’s antiepileptic medicine regimen, reduced maintenance doses should be used in patients with significant renal functional impairment (see section 4.2).
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 or 0,10 mL/min/kg in patients with grade A, B, or C (Child–Pugh Classification) hepatic impairment, respectively, compared to 0,34 mL/min/kg in the healthy controls. Clearance of lamotrigine is reduced in patients with hepatic impairment and reduced doses should generally be used in patients with grade B or C (Child-Pugh Classification) hepatic impairment (see section 4.2).
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