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Australian Journal of Pharmacy : March 2005
APPGuide 2 0 0 5 U P D A T E inducing drugs such as carbamazepine and phenytoin, and increasing to a mean of approximately 70hours when co-administered with sodium valproate alone (see Dosage and Administration). Children (under 12 years): 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 gener- ally shorter in children than in adults with a mean of approximately 7 hours when given with enzyme inducing drugs such as carbamazepine and phenytoin, and increasing to mean values of approximately 45 to 55 hours when co-administered with sodium valproate alone (see Dosage and Administration). Elderly (65 to 76 years): 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 clinically relevant extent. After single doses appar- ent clearance decreased by 12% from 35mL/min at age 20 to 31mL/min at 70 years. The decrease after 48 weeks of treatment was 10% from 41 to 37mL/min between the young and elderly groups. In addition, phar- macokinetics of lamotrigine was studied in 12 healthy elderly subjects following a 150mg single dose. The mean clearance in the elderly (0.39mL/min/kg) lies within the range of the mean clearance values (0.31 to 0.65mL/min/kg) obtained in 9 studies with non-elderly adults after single doses of 30 to 450mg. Renal Impairment: Twelve volunteers with chronic renal failure, and another 6 individuals undergoing hemodialysis were each given a single 100mg dose of lamotrigine. Mean CL/F were 0.42mL/min/kg (chronic renal failure), 0.33mL/min/kg (between hemodialysis), and 1.57mL/min/kg (during hemodialysis) compared to 0.58mL/min/kg in healthy volunteers. Mean plasma half-lives were 42.9hours (chronic renal failure), 57.4hours (between hemodialysis) and 13.0hours (during hemodialysis), compared to 26.2hours 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 hemodialysis session. For this patient population, initial doses of lamotrigine should be based on patients’ antiepileptic drugs (AEDs) regimen; reduced maintenance doses may be effective for patients with significant renal functional impairment (see Precautions). Hepatic Impairment: A single-dose pharmacokinetic study was performed in 24 subjects with various degrees of hepatic impairment and 12 healthy subjects as controls. The median apparent clearance of lamot- rigine was 0.31, 0.24 or 0.10mL/min/kg in patients with Grade A, B or C (Child-Pugh Classification) hepatic impairment, respectively, compared to 0.34mL/min/kg in the healthy controls. Reduced doses should gener- ally be used in patients with Grade B or C hepatic impairment (see Dosage and Administration). Clinical Trials: Adult Add-on Treatment of Partial and Generalised Seizures: The effi- cacy and safety of lamotrigine has been demonstrated in 6 double blind, placebo controlled, crossover studies (n=221) with duration of lamotrigine treatment ranging from 8 - 12 weeks, using doses up to 400mg. Additionally, a double blind, placebo controlled, parallel study was performed of 2 fixed doses of lamotrigine (300mg, n=71; 500mg, n=72) versus placebo (n=73). The median percentage reduction in total seizure count on lamotrigine compared with placebo significantly favoured lamotrigine in 5 of the 6 crossover trials. Overall 23% (range 7 - 67%) of patients in the controlled crossover trials showed a = 50 % reduction in total seizures in lamotrigine compared with placebo. In the controlled parallel study, the median reduction (%) from base- line in total seizures during weeks 13 - 24 was 14% on placebo compared with 23% on lamotrigine 300mg and 32% on lamotrigine 500mg. The difference from placebo was statistically significant for lamotrigine 500mg but not for lamotrigine 300mg. The commonest adverse experiences affected the central nervous system (ataxia, dizziness, diplopia) and occurred more frequently on 500mg lamot- rigine than 300mg lamotrigine in the controlled parallel study. 216 ? THE AUSTRALIAN JOURNAL OF PHARMACY VOL.86 MARCH 2005 Across the controlled trials, approximately 10% of patients on lamotrig- ine developed a rash compared with 5% on placebo, with approximately 3% of patients on lamotrigine withdrawing with this adverse experience. Adult Monotherapy: Two 48 week, double blind, randomised, active controlled (carbamazepine and phenytoin respectively) clinical trials of lamotrigine monotherapy, in the treatment of newly diagnosed epilepsy, have been conducted. An additional randomised, active controlled (carbamazepine), open trial in this patient population has also been conducted. A total of 784 patients from these three studies were analysed (443lamotrigine, 246 carbamazepine and 95 phenytoin). These studies indicate that the efficacy of lamotrigine monotherapy, in both generalised and partial seizures, may be comparable to that seen with carbamazepine and phenytoin. The escalation dose of lamotrigine in these studies that was associated with the lowest incidence of rash leading to withdrawal (2.2%) was 25mg daily for the first two weeks, followed by 50mg daily for the next two weeks, to achieve a mainte- nance dose of 100 to 200mg/day by weeks 5-6 (see Drug Interactions and Adverse Events). Paediatric Add-on Therapy: The safety and efficacy of lamotrigine has been demonstrated in 285 children with refractory epilepsy aged 2 to 12 years in 5 open add-on trials of 48 weeks duration. Lamotrigine appeared effective in both partial and generalised seizure types. Across all seizure types, 34% of patients experienced = 50% reduction in seizures. The modal maintenance dose was 5 - 15mg/kg for those not taking valproate and 1 - 5mg/kg for those taking valproate. 7% of patients discontinued lamotrigine with a rash. In patients on concomi- tant valproate, 2% withdrew with a rash when their daily dose of lamot- rigine in the first week of treatment was = 0.5mg/kg compared with 13% withdrawn with rash at an initial dose of Lamotrigine >0.5mg/kg. 155 patients aged 2 to 18 years (123 patients aged 12 years or under) continued to receive lamotrigine for up to 4 years. 4% of these patients withdrew because of adverse experiences. Lamotrigine had no effect on expected normal weight and height increase when taken for periods of up to 4 years. Lennox-Gastaut Syndrome: Lamotrigine may be of benefit as add-on therapy for seizures associated with Lennox-Gastaut Syndrome. One double blind, placebo controlled, add-on, parallel study has been performed in patients aged 3 to 25 years with Lennox-Gastaut syndrome. These patients were being treated with a combination of up to 3 antiepileptic drugs including carbamazepine, clobazam, clon- azepam, diazepam, ethosuxumide, lorazepam, nitrazepam, oxcar- bazepine, phenobarbitone, primidone, phenytoin, sodium valproate or vigabatrin. There are no data available on the use of lamotrigine as the sole drug treatment of Lennox-Gastaut Syndrome. No single drug is likely to be of benefit. After a 4 week run in period, patients (age range 2 - 28 years) were randomised to receive either lamotrigine (n=79) (age range 3 - 25) or placebo (n=90) for 16 weeks (including dose escalation period in the first 6 weeks of treatment) in addition to their existing therapy. Addi- tion of lamotrigine to existing therapy resulted in a median reduction in counts of major motor seizures (drop attacks and tonic-clonic seizures) of 32% compared with a reduction of 9% in patients on existing therapy with add-on placebo. The results were also signifi- cantly in favour of lamotrigine when drop attacks and generalised tonic-clonic seizures were analysed separately, but not for atypical absence seizures. Rash was recorded in 7/79 lamotrigine add-on patients versus 4/90 placebo add-on patients. 4 % of add-on lamotrig- ine patients and 8 % of add-on placebo patients were withdrawn with adverse experiences. 3% discontinued lamotrigine because of rash compared with 1% on placebo. In the lamotrigine group, one patient was hospitalised because of rash and a second was reported to have developed Stevens-Johnson syndrome but did not require hospitalisa- tion. 4% of patients on placebo and no patients on lamotrigine were withdrawn because of worsening seizures. AUSTRALIAN PRESCRIPTION PRODUCTS GUIDE SUPPLEMENT