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PubMed2000

Lamotrigine add-on for drug-resistant partial epilepsy.

BACKGROUND: Epilepsy is a common neurological disorder, affecting almost 0.5 to 1% of the population. Nearly 30% of patients with epilepsy are refractory to currently available drugs. Lamotrigine is one of the newer antiepileptic drugs and is the topic of this review. OBJECTIVES: To examine the effects of lamotrigine on seizures, side effects, cognition and quality of life, when used as an add-on treatment for patients with drug-resistant partial epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trials register, the Cochrane Controlled Trials Register (Cochrane Library Issue 1, 2000), MEDLINE (January 1966 to December 1999) and reference lists of articles. We also contacted the manufacturers of lamotrigine (Glaxo-Wellcome). SELECTION CRITERIA: Randomized placebo controlled trials, of patients with drug-resistant partial epilepsy of any age, in which an adequate method of concealment of randomization was used. The studies may be double, single or unblinded. For crossover studies, the first treatment period was treated as a parallel trial. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the trials for inclusion and extracted data. Primary analyses were by intention to treat. Outcomes included 50% or greater reduction in seizure frequency, treatment withdrawal (any reason), side effects, effects on cognition, and quality of life. MAIN RESULTS: We found three parallel add-on studies and eight cross-over studies, which included 1243 patients (199 children and 1044 adults). The overall Peto's Odds Ratio (OR) and 95% confidence intervals (CIs) across all studies for 50% or greater reduction in seizure frequency was 2.71 (1.87, 3.91) indicating that lamotrigine is significantly more effective than placebo in reducing seizure frequency. The overall OR (95%CI) for treatment withdrawal (for any reason) is 1.12 (0.78, 1. 61). The 99% CIs for ataxia, dizziness, nausea, and diplopia do not include unity, indicating that they are significantly associated with lamotrigine. The limited data available preclude any conclusions about effects on cognition and quality of life, though there may be minor benefits in affect balance (happiness) and mastery. REVIEWER'S CONCLUSIONS: Lamotrigine add-on therapy is effective in reducing the seizure frequency, in patients with drug-resistant partial epilepsy. Further trials are needed to assess the long term effects of lamotrigine, and to compare it with other add-on drugs.

Anticonvulsants↗

PubMed1991

Analysis of lamotrigine and lamotrigine 2-N-glucuronide in guinea pig blood and urine by reserved-phase ion-pairing liquid chromatography.

Lamotrigine is an investigational anticonsulvant drug undergoing clinical trials. A simultaneous assay was developed to quantitate lamotrigine and its major metabolite, lamotrigine 2-N-glucuronide, from guinea pig whole blood. The extraction procedure and reversed-phase high-performance liquid chromatographic (HPLC) assay employed sodium dodecylsulfate (SDS) as an ion-pairing reagent to selectively separate lamotrigine and lamotrigine 2-N-glucuronide from endogenous blood components, other anti-convulsant drugs, and their metabolites. The mobile phase was composed of acetonitrile-50 mM phosphoric acid (pH 2.2) containing 10 mM SDS (33:67, v/v), and components were detected at 277 nm. The total coefficients of variance (C.V.) for the blood assay were less than or equal to 9.4% for lamotrigine (0.25-20.0 micrograms/ml) and less than or equal to 13.4% for the glucuronide metabolite (0.25-10.0 micrograms/ml). Separate assays for lamotrigine and its glucuronide in urine were developed. In order to quantitate low levels of lamotrigine in guinea pig urine, lamotrigine was extracted with tert.-butyl methyl ether-ethyl acetate (1:1). The total C.V. for lamotrigine quantitation in urine was less than or equal to 7.5% (0.10-10.0 micrograms/ml). For the determination of lamotrigine 2-N-glucuronide, urine was diluted with an SDS-phosphoric acid buffer (1:4) and injected directly onto the HPLC system, total C.V. less than or equal to 4.2% (0.5-50 micrograms/ml).

Animals↗

PubMed2005

In vivo biopharmaceutical characterisation of a new formulation containing the antiepileptic drug lamotrigine in comparison to plain and dispersible/chewable lamotrigine tablets.

AIM: Two studies in healthy male volunteers were carried out to evaluate the pharmacokinetic profile of a new divisible formulation of lamotrigine (CAS 84057-84-1, Plexxo, Lamotrigin Desitin) in plasma in comparison to plain or dispersible lamotrigine tablets. METHODS: The plasma pharmacokinetics of lamotrigine were analysed after administration of single doses of 100 mg lamotrigine given as one tablet of the new formulation and either the plain or the dispersible reference formulation in two separate studies. In each study the data of 24 subjects were analysed according to the study protocol. Venous blood samples were taken at appropriate intervals up to 120 h after dosing. Concentrations of lamotrigine were determined in plasma by a validated HPLC method using UV detection. RESULTS AND CONCLUSION: In both studies, mean plasma concentration-time profiles of the new lamotrigine formulation and both reference formulations ran nearly in parallel. The pharmacokinetic mean data calculated from different subject groups of the two studies were very similar. The mean ratios of the main pharmacokinetic parameters and the corresponding 90% confidence intervals of AUC(0-t), AUC(0-inf) and C(max) were 103% (99.7-105.7), 103% (99.6-107.3) and 101% (95.2-106.6) for the comparison with the plain lamotrigine tablet and 100% (98.0-102.8), 100% (96.5-102.8) and 102% (99.1-105.3) for the comparison with the dispersible/chewable tablet, respectively. The most frequently reported adverse events possibly related to the administration of lamotrigine were headache and dizziness in both studies. It is concluded that the new divisible lamotrigine formulation is bioequivalent with regard to rate and extent of absorption to both the plain reference lamotrigine product and to the dispersible/chewable reference product.

Adolescent↗

PubMed1997

Concentrations of lamotrigine in a mother on lamotrigine treatment and her newborn child.

OBJECTIVE: To investigate the transfer of lamotrigine in pregnancy and during lactation from a mother on lamotrigine treatment to her child. METHODS: Concentrations of lamotrigine were measured by high-pressure liquid chromatography in umbilical cord serum and in serum samples of the mother and her child as well as in the mother's milk during the first five postpartum months. RESULTS: In the child lamotrigine serum concentrations (up to 2.8 micrograms ml-1) comparable to those usually achieved in active treatment with lamotrigine were found not only after birth, but also during lactation. A considerable amount of lamotrigine (2-5 mg per day) was excreted in breast milk. No adverse effects were seen in the child. CONCLUSION: The transfer of lamotrigine taking place during pregnancy and lactation should not be neglected. In this case the child should be thoroughly observed for potential adverse effects.

Adult↗

PubMed1993

Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. U.S. Lamotrigine Protocol 0.5 Clinical Trial Group.

We evaluated the efficacy and safety of lamotrigine (300 and 500 mg/day) as add-on therapy in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of 216 patients with refractory partial seizures. During 6 months of treatment, median seizure frequency decreased by 8% with placebo, 20% with 300 mg lamotrigine, and 36% with 500 mg lamotrigine. Seizure frequency decreased by > or = 50% in one-third of the 500-mg group and one-fifth of the 300-mg group. Reductions in seizure frequency and seizure days were statistically significant, compared with placebo, for the 500-mg group but not the 300-mg group. Most adverse events were minor and resolved over time. Nine percent of patients on lamotrigine withdrew because of adverse experiences. Lamotrigine plasma concentrations appeared to be a linear function of dose, and the drug did not affect plasma concentrations of concomitant antiepileptic drugs. Lamotrigine was safe, effective, and well tolerated as add-on therapy for refractory partial seizures.

Adolescent↗

PubMed2003

Evaluation of VPA dose and concentration effects on lamotrigine pharmacokinetics: implications for conversion to lamotrigine monotherapy.

OBJECTIVE: Lamotrigine (LTG) is approved for monotherapy following withdrawal from enzyme-inducing antiepileptic drugs. LTG is also frequently used in combination with sodium valproate (VPA), and withdrawal to monotherapy in this setting is also frequently desirable. Given the known pharmacokinetic interaction between these two drugs, clinically relevant questions that should be answered include (1) at what dose and/or concentration of VPA does this interaction begin, and (2) at what dose of VPA does maximal inhibition occur. METHODS: LTG pharmacokinetics was evaluated using single-dose LTG (25 mg) given before and following low-dose VPA co-medication (125, 250, 375, 500 mg per day VPA) in healthy subjects. Serial blood samples were obtained over 120 h post-dose in order to calculate LTG kinetic parameters including area under the concentration-time curve, apparent oral clearance, elimination half-life and percent inhibition of LTG clearance at each dosage level of VPA. Pharmacodynamic modeling was used to calculate EC(50) values for this interaction. RESULTS: LTG pharmacokinetic parameters were evaluated in adult healthy female & male volunteers. Mean trough VPA concentrations at doses of 125, 250, 375 and 500 mg per day were 6.5, 13.9, 16.1 and 31.9 microg/ml, respectively. Maximal theoretical inhibition of LTG oral clearance by VPA is approximately 65%, with an EC50 concentration value of approximately 5.6 microg/ml of VPA. Mean inhibition of LTG oral clearance during concomitant treatment with VPA 125, 250, 375 and 500 mg per day was 30.8, 51.5, 52.8 and 50.3%, respectively. CONCLUSIONS: These data suggest that VPA inhibition of LTG clearance begins at very low VPA doses and concentrations. Importantly, maximal inhibition can be expected at VPA doses of approximately 500 mg per day, with the magnitude of inhibition diminishing at doses below this. These data provide useful information to develop a dosing algorithm to facilitate conversion to LTG monotherapy.

Adult↗

PubMed1999

Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group.

In a multicentre, double-blind trial 150 elderly patients (mean age 77 years) with newly diagnosed epilepsy were randomised in a 2:1 ratio to treatment with lamotrigine (LTG) or carbamazepine (CBZ). Following a short titration period, the dosage was individualised for each patient while maintaining the blind over the next 24 weeks. The main difference between the groups was the rate of drop-out due to adverse events (LTG 18% versus CBZ 42%). This was in part a consequence of the lower rash rate with LTG (LTG 3%, CBZ 19%; 95% CI 7-25%). LTG-treated patients also complained less frequently of somnolence (LTG 12%, CBZ 29%; 95% CI 4-30%). Although there was no difference between the drugs in time to first seizure, a greater percentage of LTG-treated patients remained seizure-free during the last 16 weeks of treatment (LTG 39%, CBZ 21%; P = 0.027). Overall, more patients continued on treatment with LTG than CBZ (LTG 71%, CBZ 42%; P < 0.001) for the duration of the study. The hazard ratio for withdrawal was 2.4 (95% CI 1.4-4.0) indicating that a patient treated with CBZ was more than twice as likely to come off medication than one taking LTG. In conclusion, LTG can be regarded as an acceptable choice as initial treatment for elderly patients with newly diagnosed epilepsy.

Aged↗

PubMed2006

In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction.

Studies were performed to investigate the UDP-glucuronosyltransferase enzyme(s) responsible for the human liver microsomal N2-glucuronidation of the anticonvulsant drug lamotrigine (LTG) and the mechanistic basis for the LTG-valproic acid (VPA) interaction in vivo. LTG N2-glucuronidation by microsomes from five livers exhibited atypical kinetics, best described by a model comprising the expressions for the Hill (1869 +/- 1286 microM, n = 0.65 +/- 0.16) and Michaelis-Menten (Km 2234 +/- 774 microM) equations. The UGT1A4 inhibitor hecogenin abolished the Michaelis-Menten component, without affecting the Hill component. LTG N2-glucuronidation by recombinant UGT1A4 exhibited Michaelis-Menten kinetics, with a Km of 1558 microM. Although recombinant UGT2B7 exhibited only low activity toward LTG, inhibition by zidovudine and fluconazole and activation by bovine serum albumin (BSA) (2%) strongly suggested that this enzyme was responsible for the Hill component of microsomal LTG N2-glucuronidation. VPA (10 mM) abolished the Hill component of microsomal LTG N2-glucuronidation, without affecting the Michaelis-Menten component or UGT1A4-catalyzed LTG metabolism. Ki values for inhibition of the Hill component of LTG N2-glucuronidation by VPA were 2465 +/- 370 microM and 387 +/- 12 microM in the absence and presence, respectively, of BSA (2%). Consistent with published data for the effect of fluconazole on zidovudine glucuronidation by human liver microsomal UGT2B7, the Ki value generated in the presence of BSA predicted the magnitude of the LTG-VPA interaction reported in vivo. These data indicate that UGT2B7 and UGT1A4 are responsible for the Hill and Michaelis-Menten components, respectively, of microsomal LTG N2-glucuronidation, and the LTG-VPA interaction in vivo arises from inhibition of UGT2B7.

Anticonvulsants↗

PubMedDate not supplied

Lamotrigine as add-on therapy in treatment-resistant epilepsy. Portuguese Lamotrigine as Add-on Therapy in Treatment-resistant Epilepsy Study Group.

The efficacy and safety of lamotrigine as add-on therapy in treatment-resistant epilepsy were evaluated in an open prospective study carried out at five centres in Portugal and involving 61 patients. Daily seizure diaries were kept by patients, and used by the investigators to give a rating of response to therapy. Assessments were recorded after 1, 2, 3, 6, 9, 12, 18 and 24 months. Overall, seizure control was improved in 57% of patients, remained unchanged in 34% and deteriorated in 9%. There were some indications that efficacy was greatest in patients with generalized seizures and in those taking concomitant valproate. Efficacy was maintained throughout the 2-year study. It was possible to reduce the dose of concomitant antiepileptic drug in 56% of patients, and seven patients no longer needed a concomitant antiepileptic drug. Although 75% of patients reported an adverse experience, most of these were mild or moderate in intensity, did not require treatment and were not judged to be serious. A total of 13 patients withdrew from the study (four due to adverse events, four due to lack of efficacy and five for other reasons).

Administration, Oral↗

PubMed2006

Lamotrigine adjunctive therapy among children and adolescents with primary generalized tonic-clonic seizures.

CONTEXT AND OBJECTIVE: Primary generalized tonic-clonic seizures are relatively more common among children than among adults. Primary generalized tonic-clonic seizures are associated with increased risk of injury and death. Therefore, effective control of primary generalized tonic-clonic seizures is necessary to reduce epilepsy-related morbidity and mortality. Lamotrigine has demonstrated efficacy from published randomized clinical trials for childhood partial seizures, absence seizures, and for the generalized seizures associated with Lennox-Gastaut syndrome. A randomized, blinded, placebo-controlled study was conducted to assess the efficacy and tolerability of adjunctive therapy with lamotrigine in the treatment of primary generalized tonic-clonic seizures among patients > or = 2 years of age; we report the data from children and adolescents 2 to 20 years of age from this randomized clinical trial. This is the first published analysis of data from a randomized, double-blind, controlled clinical trial of primary generalized tonic-clonic seizures focusing on children and adolescents. PATIENTS AND METHODS: We randomly assigned (1:1) 117 patients, aged 2 to 55 years, with primary generalized tonic-clonic seizures inadequately controlled on 1 to 2 current antiepileptic drugs and with evidence of primary generalized tonic-clonic seizures on electroencephalogram and no historical or electroencephalogram evidence of partial seizures to either lamotrigine or placebo in a double-blind parallel group clinical trial from 2001 through 2004. We analyzed the subgroup of children and adolescents, aged 2 to 20 years (n = 45), from this randomized clinical trial. Patients having > or = 3 primary generalized tonic-clonic seizures over an 8-week baseline were randomly assigned (1:1) to receive either lamotrigine or placebo. The treatment period consisted of an escalation phase (12 weeks for patients 2-12 years; 7 weeks for patients > 12 years) and a maintenance phase (12 weeks). The study had 4 phases: screening phase, baseline phase, escalation phase, and maintenance phase. During the screening phase, baseline medical examinations and seizure type and seizure frequency assessments were performed. During the 8-week baseline phase, the number and dosages of concomitant antiepileptic drugs were maintained while seizure frequency was assessed. The assessment of primary generalized tonic-clonic seizure frequency was determined during the 8-week baseline phase. Patients eligible for random assignment experienced > or =3 primary generalized tonic-clonic seizures during the baseline phase and > or = 1 primary generalized tonic-clonic seizure in the 8 weeks before the baseline phase. Lamotrigine was introduced and titrated using a schedule based on the patients' age and concurrent antiepileptic drug regimen. During the escalation phase, the number and doses of concomitant antiepileptic drugs were not changed. The escalation phase was followed by a 12-week maintenance phase during which time the lamotrigine dose was maintained at a specific dose defined by the patients' age and concomitant antiepileptic drugs, whereas the doses of concurrent antiepileptic drugs were maintained at a constant dose. Concurrent antiepileptic drugs could not be discontinued or added during the maintenance phase. The primary efficacy end point measure was the median reduction in the frequency of primary generalized tonic-clonic seizures from baseline; seizure counts were recorded prospectively in standardized daily seizure diaries. Other efficacy end point data for analysis were as follows: the median seizure counts, the median percentage change from the baseline phase in average monthly seizure frequency for other generalized seizure types, and the percentage of patients with a reduction of > or = 25%, > or = 50%, > or = 75%, or 100% in frequencies of primary generalized tonic-clonic seizures and all generalized seizures during the escalation phase and/or maintenance phase relative to the baseline phase. Accurate counts of absence seizure frequency require electroencephalogram-video monitoring; absence seizure frequency was not an outcome measure for this analysis. RESULTS: Forty-five (21 lamotrigine and 24 placebo) patients 2 to 19 years of age were randomly assigned and received study drug. Eight patients (3 lamotrigine and 5 placebo) had a combination of clinical (myoclonus and/or absence seizures) and electroencephalogram findings that were consistent with juvenile myoclonic epilepsy. Among the 45 children randomly assigned, 74% had generalized spike, polyspike, and/or generalized spike and wave discharges on routine electroencephalogram recordings; the remaining 26% of children had no electroencephalogram findings suggestive of partial epilepsy and a clear history consistent with primary generalized tonic-clonic seizures. Electroencephalogram findings were not significantly different between the lamotrigine and the placebo treatment groups. The median percentage decrease from baseline in primary generalized tonic-clonic seizures during the entire treatment period was 77% in the lamotrigine group and 40% in the placebo group (P = .044). The median primary generalized tonic-clonic seizure counts per month were 0.7 in the lamotrigine group and 3.6 in the placebo group during escalation (P = .008), 0.3 in the lamotrigine group and 2.0 in the placebo group during maintenance (P = .005), and 0.4 in the lamotrigine group and 2.5 in the placebo group during the entire treatment period (P = .007). Trends were noted during escalation and maintenance with a median percentage decrease in primary generalized tonic-clonic seizures during escalation of 72% in the lamotrigine group and 30% in the placebo group (P = .059), and 83% in the lamotrigine group and 42% in the placebo group during maintenance (P = .058). During the maintenance phase, 48% of lamotrigine patients were seizure free compared with 17% treated with placebo (P = .051). One patient from each treatment group discontinued from the study because of an adverse event; 1 patient who received lamotrigine experienced "disorientation"; and 1 patient who received placebo had a convulsion with apnea. No rashes occurred among patients taking lamotrigine or placebo. No patient experienced worsening of the intensity or frequency of myoclonus. CONCLUSIONS: Adjunctive lamotrigine therapy seems effective in controlling primary generalized tonic-clonic seizures among patients 2 to 20 years of age.

Adolescent↗

PubMed2005

Effect of antiepileptic drug comedication on lamotrigine clearance.

OBJECTIVE: To investigate the effect of antiepileptic drug (AED) comedication, including all newer AEDs, on lamotrigine clearance (CL). DESIGN: We reviewed 570 medical charts of outpatients 12 years and older seen at the Columbia Comprehensive Epilepsy Center who received lamotrigine as monotherapy or adjunctive therapy. We investigated whether a given comedication contributed to the lamotrigine serum concentration. In addition, we examined whether the mean lamotrigine CL during comedication with each AED differed from the lamotrigine CL during monotherapy. Finally, we examined whether individuals had significantly different lamotrigine CLs when taking or not taking a particular comedication. RESULTS: Comedication with phenytoin, carbamazepine, and valproate sodium were the major AED predictors of lamotrigine serum concentration. Comedication regimens with felbamate, oxcarbazepine, and phenobarbital were small but significant predictors. The mean lamotrigine CL was 43.2 mL/h per kilogram of body weight with lamotrigine monotherapy, significantly higher with comedication with phenytoin (101.3 mL/h per kilogram) and carbamazepine (59.5 mL/h per kilogram) and significantly lower with valproate (16.9 mL/h per kilogram). Patients had significantly higher lamotrigine CL when taking phenytoin, carbamazepine, and phenobarbital than when not taking those comedications and had significantly lower lamotrigine CL when taking valproate. The mean lamotrigine CL was significantly lower than that associated with monotherapy in patients comedicated with valproate plus phenytoin (22.0 mL/h per kilogram) but not in patients comedicated with valproate plus carbamazepine (33.3 mL/h per kilogram). No other AEDs affected lamotrigine CL. CONCLUSION: Phenytoin increases lamotrigine CL by approximately 125%, carbamazepine increases lamotrigine CL by approximately 30% to 50%, and valproate decreases lamotrigine CL by approximately 60%. No newer AED, with the possible exception of oxcarbazepine, has a major impact on lamotrigine CL.

Adolescent↗

PubMed2003

Lamotrigine: a review of its use in bipolar disorder.

UNLABELLED: Lamotrigine (Lamictal), a phenyltriazine derivative, is a well established anticonvulsant agent that has shown efficacy in the prevention of mood episodes in adult patients with bipolar I disorder. The mechanism of action of the drug in patients with bipolar disorder may be related to the inhibition of sodium and calcium channels in presynaptic neurons and subsequent stabilisation of the neuronal membrane. Lamotrigine monotherapy significantly delayed time to intervention with additional pharmacotherapy or electroconvulsive therapy for any new mood episode (mania, hypomania, depression and mixed episodes), compared with placebo, in two large, randomised, double-blind trials of 18 months' duration. Additionally, lamotrigine was significantly superior to placebo at prolonging time to intervention for depression. These effects of lamotrigine were demonstrated in both recently manic/hypomanic and recently depressed patients. Lamotrigine showed efficacy in delaying manic/hypomanic episodes in pooled data only, although lithium was superior to lamotrigine on this measure. Two of four double-blind, short-term studies have shown lamotrigine to be more effective than placebo in the treatment of patients with treatment-refractory bipolar disorder or those with bipolar depression. Lamotrigine has not demonstrated efficacy in the treatment of acute mania. Lamotrigine was generally well tolerated in maintenance studies with the most common adverse events being headache, nausea, infection and insomnia. Incidences of diarrhoea and tremor were significantly lower in lamotrigine- than in lithium-treated patients. The incidence of serious rash with lamotrigine treatment was 0.1% in all studies of bipolar disorder and included one case of mild Stevens-Johnson syndrome. Lamotrigine did not appear to cause bodyweight gain. The dosage of lamotrigine is titrated over a 6-week period to 200 mg/day to minimise the incidence of serious rash. Adjustments to the initial and target dosages are required if coadministered with valproate semisodium or carbamazepine. CONCLUSION: Lamotrigine has been shown to be an effective maintenance therapy for patients with bipolar I disorder, significantly delaying time to intervention for any mood episode. Additionally, lamotrigine significantly delayed time to intervention for a depressive episode and showed limited efficacy in delaying time to intervention for a manic/hypomanic episode, compared with placebo. Although not approved for the short-term treatment of mood episodes, lamotrigine has shown efficacy in the acute treatment of patients with bipolar depression but has not demonstrated efficacy in the treatment of acute mania. Lamotrigine is generally well tolerated, does not appear to cause bodyweight gain and, unlike lithium, generally does not require monitoring of serum levels.

Antimanic Agents↗

PubMed2004

Spotlight on lamotrigine in bipolar disorder.

Antidepressive Agents↗

PubMed2006

Lopinavir/ritonavir reduces lamotrigine plasma concentrations in healthy subjects.

BACKGROUND: Limited data are available about the effect of lopinavir and low-dose ritonavir on glucuronidation. Lamotrigine undergoes glucuronidation. We studied the effect of lopinavir/ritonavir on the pharmacokinetics of lamotrigine and vice versa. METHODS: Twenty-four healthy subjects received 50 mg lamotrigine once daily on days 1 and 2 and 100 mg twice daily on day 3 through day 23. Lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) was added on day 11. Depending on the decrease in lamotrigine trough level between days 10 and 20, either the study was stopped (<20% decrease) or a dose increase was applied from day 23 to day 31, as follows: increase to 150 mg lamotrigine twice daily if there was a 20% to 33% decrease, increase to 200 mg twice daily if there was a 34% to 66% decrease, and increase to 300 mg twice daily if there was a greater than 66% decrease. On days 10, 20, and 31, 12-hour pharmacokinetic curves were drawn. RESULTS: The mean decrease in lamotrigine trough level between days 10 and 20 was 55.4% (n = 18). A dose increment to 200 mg lamotrigine twice daily was used in all subjects. The area under the plasma concentration-time curve (AUC) values of lamotrigine on day 20 (with lopinavir/ritonavir) and day 10 (without lopinavir/ritonavir) were bioinequivalent, with a point estimate of 0.50 (90% confidence interval, 0.47-0.54). After dose adjustment of lamotrigine to 200 mg twice daily, the AUC on day 31 (n = 15) was bioequivalent to that on day 10, with a point estimate of 0.91 (90% confidence interval, 0.82-1.02). The median AUC ratios of lamotrigine 2N-glucuronide to lamotrigine on day 10 and day 20 were 0.57 (interquartile range, 0.39-0.75) and 1.12 (interquartile range, 0.87-1.31). Pharmacokinetic parameters for lopinavir/ritonavir were similar to historical controls. CONCLUSION: Lopinavir/ritonavir decreases the AUC of lamotrigine, probably by induction of glucuronidation. A dose increment to 200% of the initial lamotrigine dose is needed to achieve concentrations similar to those with lamotrigine alone. Lamotrigine does not appear to affect the pharmacokinetics of lopinavir/ritonavir.

Adolescent↗

PubMed2004

Diffusion of the new antiepileptic drug lamotrigine in Dutch clinical practice.

INTRODUCTION: Lamotrigine is one of the recently introduced antiepileptic drugs (AEDs) licensed in the Netherlands in 1995. The objective of this study was to examine the diffusion of lamotrigine into clinical practice. Three different aspects of this diffusion process were examined: incidence of use, patient characteristics and changes in prescription patterns in the first 5 years following its introduction. METHODS: A retrospective follow-up study has been conducted using drug prescription data from the database of the Dutch Drug Information Project (GIP database). Patients were included who started with lamotrigine, carbamazepine, phenytoin or valproate in the period between January 1996 and December 2000. Incidence of use was calculated for the four drugs. Multiple logistic regression analysis was used to determine differences in baseline characteristics. The Chi-square test was used to analyse changes in the usage patterns of lamotrigine. RESULTS: The study population consisted of a total of 29,718 patients who were prescribed carbamazepine, phenytoin, valproate or lamotrigine for the first time in the study period. Carbamazepine and valproate accounted for the majority of all new prescriptions; the incidence of lamotrigine use remained stable with 4.4 patients per 100,000 per year. Baseline characteristics of lamotrigine differed depending on the patient's age and gender (OR 3.7, 95% CI 3.3-4.2; OR 1.4, 95% CI 1.3-1.5) relative to the conventional AEDs. In a large majority of cases, lamotrigine was used as a second-line or third-line AED. Physicians prescribing lamotrigine were predominantly neurologists, in contrast to prescribers of conventional AEDs. The prevalence of psychotropic medication and migraine-abortive drugs was significantly lower in users of lamotrigine than in users of conventional AEDs. During follow-up, several significant trends were noticed in the prescribing of lamotrigine with regard to age groups, gender, antiepileptic history and off-label use. DISCUSSION: Lamotrigine is prescribed to a population different from that using conventional AEDs. The uptake of lamotrigine in clinical practice is slow, for reasons probably related to characteristics of the drug itself and the prescribers. During the observation period, lamotrigine diffused gradually towards more first-line use as an AED and more off-label use.

Adolescent↗

PubMed2005

A dosing algorithm for converting from valproate monotherapy to lamotrigine monotherapy in patients with epilepsy.

A dosing algorithm was used to guide the conversion of 77 patients with epilepsy (16 years of age) from valproate monotherapy through lamotrigine adjunctive therapy at 200mg daily to lamotrigine monotherapy at 500 mg daily in an open-label study comprising a lamotrigine escalation phase (8 weeks), a valproate withdrawal phase (6 weeks), and a lamotrigine monotherapy phase (4 weeks). The algorithm was designed to maintain stable trough concentrations of lamotrigine during valproate withdrawal to minimize seizure risk. Of the 77 patients, 11 prematurely withdrew for administrative reasons (noncompliance, consent withdrawn, loss to follow-up, protocol violation). Of the remaining 66 patients, 18 withdrew because of adverse events, and 48 completed the study. Among the 67 patients with at least one lamotrigine trough serum concentration after initiation of therapy (pharmacokinetic population), mean trough serum concentrations at the end of the lamotrigine escalation phase at a lamotrigine daily dose of 200 mg (7.9 microg/mL, SD = 3.3) did not differ significantly from values during the valproate withdrawal phase (8.7 microg/mL, SD = 3.5) and the lamotrigine monotherapy phase at a lamotrigine dose of 500 mg daily (7.2 microg/mL, SD = 3.3). A similar pattern of results was observed among the 34 patients who completed the study on lamotrigine (completer population). No serious rashes were reported, and the incidence of withdrawals because of decreased seizure control was low (n = 2, or 3%; both incidents were judged to be related to noncompliance). By employment of a four-step dosing algorithm, lamotrigine serum concentrations can be maintained at a stable level with favorable tolerability during a transition from lamotrigine 200mg daily as adjunctive therapy with valproate to lamotrigine monotherapy 500 mg daily.

Adolescent↗

PubMed1996

Bidirectional interaction of valproate and lamotrigine in healthy subjects.

OBJECTIVE: To evaluate the steady-state pharmacokinetics of lamotrigine and valproate at three dosing levels of lamotrigine in normal volunteers receiving steady-state therapeutic doses of valproate. METHODS: This was an open-label, randomized, three-way crossover study of 18 normal male volunteers. Subjects received oral valproate (500 mg Depakote twice a day) throughout the study. Each subject subsequently received three oral dosage regimens of lamotrigine (50, 100, or 150 mg/day) for 1 week each, with a 2-week washout period between lamotrigine treatment periods. Valproate and lamotrigine trough plasma samples were determined by a capillary gas chromatography method and immunofluorometric assay, respectively. Urine samples were assayed for 11 valproate metabolites by gas chromatography/mass spectrometry. RESULTS: When compared to other studies in which lamotrigine was administered with no concurrent antiepileptic drug, concomitant valproate markedly increased the half-life of lamotrigine and decreased lamotrigine clearance, without substantial alteration in the linear kinetics of the drug. The addition of lamotrigine was associated with a small but significant 25% decrease in steady-state valproate plasma concentration. Oral clearance of valproate was increased (from 7.2 +/- 1.1 ml/hr/kg before lamotrigine treatment to 9.0 +/- 2.0 ml/hr/kg on day 28; p < 0.05). The formation clearance of the hepatotoxic valproate metabolites, 2-n-propyl-4-pentenoic acid (4-ene-valproate) and 2-propyl-2,4-pentadienoic acid [2(E),4-diene-valproate], was unaffected by lamotrigine administration. CONCLUSIONS: As a consequence of the interaction between lamotrigine and sodium valproate, a dosage reduction of lamotrigine should be considered in patients taking a combination of valproate and lamotrigine.

Analysis of Variance↗

PubMed2006

Lamotrigine combined with divalproex or lithium for bipolar disorder: a case series.

OBJECTIVE: To assess the efficacy of lamotrigine combined with either divalproex or lithium for the treatment of bipolar disorder. INTRODUCTION: Lithium and divalproex seem to be predominantly effective for manic and mixed symptoms of bipolar disorder, whereas lamotrigine may be more effective for bipolar depression than for mania. Combination therapy may provide more efficacious treatment for many patients with bipolar disorder. METHODS: Data from charts of adult outpatients with bipolar disorder treated with lamotrigine plus divalproex or lithium during a 3-year period were retrospectively analyzed. The Clinical Global Impressions for Bipolar Disorder scale was used to assess severity of illness at baseline (adjunct-therapy initiation) and improvement after 3 months of treatment. The safety and tolerability of the medication combinations were assessed. RESULTS: After 3 months of treatment, 26 of 39 patients (67%) receiving lamotrigine plus divalproex had a depression rating of 1 (very much improved) or 2 (much improved) compared with seven of 16 (44%) taking lamotrigine plus lithium. The mania rating was 1 or 2 for 13 of 39 (39%) patients treated with lamotrigine plus divalproex and 7 of 16 (44%) patients receiving lamotrigine plus lithium. For overall illness severity, 26 of 39 (67%) patients given lamotrigine plus divalproex had scores of 1 or 2 compared with 10 of 16 (62%) patients taking lamotrigine plus lithium. Five of 39 patients (13%) taking lamotrigine plus divalproex and 5 of 16 (31%) receiving lamotrigine plus lithium discontinued at least one part of the combination in <3 months due to adverse events. CONCLUSION: Combination therapy with lamotrigine plus divalproex or lithium may be a valuable option for managing symptoms of bipolar disorder. The combinations were generally well tolerated and apparently effective in improving depression as well as mania. The percentage of patients showing improvement in depression was somewhat larger. Tolerability was somewhat better for lamotrigine plus divalproex in combination than for lamotrigine plus lithium. Differences in tolerability are consistent with studies indicating poorer tolerability of lithium compared with divalproex.

Adolescent↗