Advantages and problems with pregnancy registries: observations and surprises throughout the life of the International Lamotrigine Pregnancy Registry.

PURPOSE: The International Lamotrigine Pregnancy Registry monitored for a signal of a substantial increase in the frequency of major congenital malformations associated with lamotrigine exposures in pregnancy over an 18-year period. Key methodological lessons are discussed. METHODS: The strengths and weaknesses of the Registry were assessed using quantifiable methodological and operational parameters including enrollment, completeness of exposure and outcome data reporting, and lost to follow-up. The choice of comparator groups and stopping rules for registry closure were critically evaluated. RESULTS: The reliance on voluntary reporting was associated with a clustered geographical distribution of registered pregnancies. The enrollment rate increased over time with new approvals and indications for lamotrigine and publication of interim data. Reporter burden was minimized through a streamlined data collection approach resulting in a high level of completeness of exposure and primary outcome data. Lost to follow-up rates were high (28.5% overall) representing a major limitation; incentives to increase the completeness of reporting failed to reduce rates. A lack of an internal comparator group complicated data interpretation; but external comparisons with multiple external groups allowed an assessment of consistency of outcome data across multiple data sources. A lack of a priori closure criteria prolonged the life of the Registry, and consideration of regulatory guidelines on this subject is encouraged at the time of conception of future registries. CONCLUSIONS: A successful pregnancy exposure registry requires ongoing flexibility and continuous re-assessment of enrollment, recruitment, and retention methods and the availability of comparison data, throughout its lifecycle.

Assessing impact of real-world dosing irregularities with lamotrigine extended-release and immediate-release formulations by pharmacokinetic simulation.

PURPOSE: To assess the effect of common dosing irregularities on serum concentrations of antiepileptic drug (AED) lamotrigine for the extended-release (XR) formulation, which is recommended for once-daily dosing (QD), and the immediate-release (IR) formulation, which is typically dosed twice daily (BID). METHODS: A pharmacokinetic model was constructed for lamotrigine XR and IR formulations in the presence and absence of comedications. The model was then used to simulate concentration time profiles in scenarios of full compliance and various forms of nonadherence such as a delayed dose, a missed dose, and a doubled dose. RESULTS: Lamotrigine steady-state serum concentrations stayed in a narrower range for XR-QD than for IR-BID, despite the more frequent dosing of the latter. At the same daily dose, concentrations with IR-BID were outside the range seen with XR-QD for the majority of the day. For XR-QD, concentration decrease due to dosing delay was small (<15%) when the delay was up to 4, 8, and 16 hours in patients receiving enzyme-inducing AEDs, neutral AEDs, and enzyme inhibitor valproate, respectively. For IR-BID, similar concentration decrease was caused by shorter delay. A single missed dose caused a notable 16%-68% trough concentration reduction, which was broadly comparable between XR-QD and IR-BID for each AED group. A doubled dose after a missed dose did not lead to excessive peak concentration for either treatment. CONCLUSIONS: Simulations have provided quantitative insight, showing that XR formulation is generally more forgiving in nonadherence. They also suggest that in a typical patient, a missed dose should be made up by doubling the next dose. The approach illustrates how a model constructed on clinical trial data can be used to simulate real-world dosing scenarios and guide therapeutics.

Adjunctive Transdermal Cannabidiol for Adults With Focal Epilepsy: A Randomized Clinical Trial.

Importance: Cannabidiol has shown efficacy in randomized clinical trials for drug-resistant epilepsy in specific syndromes that predominantly affect children. However, high-level evidence for the efficacy and safety of cannabidiol in the most common form of drug-resistant epilepsy in adults, focal epilepsy, is lacking. Objective: To investigate the efficacy, safety, and tolerability of transdermally administered cannabidiol in adults with drug-resistant focal epilepsy. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, multicenter clinical trial at 14 epilepsy trial centers in Australia and New Zealand. Participants were adults with drug-resistant focal epilepsy receiving a stable regimen of up to 3 antiseizure medications. Data were analyzed from July 2017 to November 2018. Interventions: Eligible participants were randomized (1:1:1) to 195-mg or 390-mg transdermal cannabidiol or placebo twice daily for 12 weeks, after which they could enroll in an open-label extension study for up to 2 years. Main Outcomes and Measures: Seizure frequency was self-reported using a daily diary. The primary efficacy end point was the least squares mean difference in the log-transformed total seizure frequency per 28-day period, adjusted to a common baseline log seizure rate, during the 12-week treatment period. Results: A total of 188 patients (45% male [85 patients] and 54.8% female [103 patients]) with a mean (SD) age of 39.2 (12.78) years were randomized, treated, and analyzed (195-mg cannabidiol, 63 participants; 390-mg cannabidiol, 62 participants; placebo, 63 participants). At week 12 of the double-blind period, there was no difference in seizure frequency between placebo (mean [SD] 2.49 [1.31] seizures per 28 days) and 195-mg cannabidiol (mean [SD] 2.51 [1.15] seizures per 28 days; least squares mean difference, 0.014; 95% CI, -0.175 to 0.203; P = .89) or 390-mg cannabidiol (mean [SD] 2.59 [1.12] seizures per 28 days; least squares mean difference, 0.096; 95% CI, -0.093 to 0.285; P = .32). By month 6 of the open-label extension, 115 patients (60.8%) achieved a seizure reduction of at least 50%. Treatment-emergent adverse events occurred in 50.4% (63 of 125 participants) of the cannabidiol group vs 41.3% (26 of 63 participants) in the placebo group, with a treatment difference of 9.1% (95% CI, -6.0% to 23.6%), and occurred at similar rates in the cannabidiol groups. Few participants discontinued (7% [14 of 188 participants]), and most (98% [171 of 174 participants]) continued into the open-label extension. Conclusions and Relevance: Both doses of transdermal cannabidiol were well tolerated and safe. No significant difference in efficacy was observed between cannabidiol and placebo during the double-blind treatment period. The open-label extension demonstrated the long-term safety, tolerability, and acceptability of transdermal cannabidiol delivery. Trial Registration: ACTRN12616000510448 (double-blind); ACTRN12616001455459 (open-label).

Effects of lamotrigine and phenytoin on the pharmacokinetics of atorvastatin in healthy volunteers.

PURPOSE: Statins and antiepileptic drugs (AEDs) are frequently coprescribed to individuals with hypercholesterolemia and new-onset seizures. Statins are metabolized by the cytochrome P450 (CYP) enzyme system. Interactions between statins and agents that undergo CYP metabolism are common. In this study, the effects of two commonly prescribed AEDs, lamotrigine and phenytoin, with different routes of metabolism (CYP3A4 versus glucuronic acid conjugation) on atorvastatin pharmacokinetics were evaluated. METHODS: Healthy volunteers (n=119) received atorvastatin 40 mg/day for 7 days followed by addition of lamotrigine (target 300 mg/day) or phenytoin (target ~4 mg/kg per day) in this open-label, single-sequence, two-cohort study. Serial pharmacokinetic sampling of atorvastatin was conducted on day 7 of atorvastatin dosing and day 70 of lamotrigine + atorvastatin dosing or day 28 of phenytoin + atorvastatin dosing. Main outcome measures were steady-state area under the curve over the 24-h dosing interval (AUC((0-τ)) ) and maximum concentration (C(max) ) of atorvastatin and its metabolites, 2OH-atorvastatin and 4OH-atorvastatin, in the presence of lamotrigine or phenytoin. KEY FINDINGS: When atorvastatin was administered with lamotrigine compared with when atorvastatin was administered alone, atorvastatin AUC((0-τ)) was within bounds indicating no interaction, whereas C(max) was slightly higher(14%); AUC((0-τ)) and C(max) were 3% and 20% higher, respectively, for 2OH-atorvastatin and 25% and 21% higher, respectively, for 4OH-atorvastatin.When atorvastatin was administered with phenytoin compared with when atorvastatin was administered alone, reductions in AUC((0-τ)) and C(max) were observed for atorvastatin (54% and 24%, respectively), 2OH-atorvastatin (53% and 22%, respectively), and 4OH-atorvastatin (44% and 52%, respectively). SIGNIFICANCE: Pharmacokinetics of atorvastatin were not significantly affected by coadministration with lamotrigine. Phenytoin significantly reduced atorvastatin bioavailability. Consistent with the published literature, these data are consonant with the possibility that atorvastatin does not require dose adjustment when coadministered with lamotrigine at doses to 300 mg/day, whereas atorvastatin coadministered with phenytoin may require atorvastatin dose adjustment to maintain atorvastatin exposure.

Safety and Tolerability of Transdermal Cannabidiol Gel in Children With Developmental and Epileptic Encephalopathies: A Nonrandomized Controlled Trial.

Importance: Developmental and epileptic encephalopathies (DEEs) are the most severe group of drug-resistant epilepsies. Alternatives to oral therapies are urgently needed to reduce seizures and improve developmental outcomes and comorbidities in this medically complex population. Objective: To assess the safety and tolerability of cannabidiol (CBD) transdermal gel in children with DEEs and to evaluate seizure frequency, sleep, and quality of life. Design, Setting, and Participants: This nonrandomized controlled trial was conducted in 2 centers in Australia and New Zealand from April 2018 to July 2019. Children and adolescents aged 3 to 18 years with DEEs who were receiving a stable regimen of 1 to 4 antiseizure medications were eligible for this study. After 1-month baseline and titration periods, patients entered a 5.5-month flexible-dosing maintenance period for a total of 6.5 months of treatment. Data were analyzed throughout the 6.5-month treatment period. Interventions: Twice-daily applications of CBD transdermal gel at doses of 125 to 500 mg for 6.5 months. Main Outcomes and Measures: Safety and tolerability assessments included adverse events (AEs) and examination of skin. The outcome for seizures was the median percentage change from baseline in monthly (28-day) seizure frequency of focal impaired awareness seizures (FIAS) and tonic-clonic seizures (TCS) over 6.5 months. Results: Of 48 patients (mean [SD] age, 10.5 [3.8] years; 26 [54%] boys), 29 (60%) had at least 1 treatment-related AE over 6.5 months; 44 of 46 treatment-related AEs (96%) were mild or moderate. Treatment-related AEs that occurred in at least 5% of patients were application-site dryness, application-site pain, and somnolence (each reported by 4 patients [8%]). The only treatment-related gastrointestinal AE was diarrhea, reported in a single patient. CBD treatment was associated with reductions in FIAS and TCS frequency. Analysis of the 33 patients with FIAS and TCS showed a median (interquartile range) monthly reduction in seizures of 58% (-5.3% to 81.8%) at 5 months and 43.5% (-23.8% to 57.5%) over the entire 6.5-month study period. Parents and caregivers noted improvements in social or interpersonal engagement and irritability (33 of 43 [77%] participants); alertness, energy, and sleep (23 of 43 [53%]); and cognition or concentration (20 of 43 [47%]). Conclusions and Relevance: In this study, CBD transdermal gel was safe, well tolerated, and was associated with reductions in FIAS and TCS frequency and disease burden. Trial Registration: ClinicalTrials.gov Identifier: ACTRN12618000516280.

Adjunctive lamotrigine XR for primary generalized tonic-clonic seizures in a randomized, placebo-controlled study.

Efficacy and tolerability of once-daily adjunctive lamotrigine extended-release (XR) for primary generalized tonic-clonic (PGTC) seizures in epilepsy were evaluated. Patients (n = 153) ≥ 13 years old diagnosed with epilepsy with PGTC seizures were randomized to once-daily adjunctive lamotrigine XR or placebo in a double-blind, parallel-group trial comprising a baseline phase, a 7-week double-blind escalation phase, and a 12-week double-blind maintenance phase. Lamotrigine XR was more effective than placebo with respect to median percentage reduction from baseline in weekly PGTC seizure frequency (primary endpoint-19-week treatment phase: 75.4% vs 32.1%, P<0.0001; escalation phase: 61.9% vs 30.6%, P = 0.0016; maintenance phase: 89.7% vs 33.3%, P<0.0001). Lamotrigine XR was more effective than placebo with respect to the percentage of patients with ≥50% reduction in PGTC seizure frequency. Significant separation from placebo for ≥50% reduction in PGTC seizures was observed beginning on treatment day 8. The most common adverse event was headache (lamotrigine XR 14%, placebo 16%).

Effects of lamotrigine compared with levetiracetam on anger, hostility, and total mood in patients with partial epilepsy.

PURPOSE: To assess anger/hostility during treatment with lamotrigine adjunctive therapy versus levetiracetam adjunctive therapy in patients with partial seizures. METHODS: This randomized, double-blind, parallel-group study in adults with partial seizures included an 8-week escalation phase, during which adjunctive lamotrigine (n = 132) or adjunctive levetiracetam (n = 136) was titrated to a target dose, and a 12-week, double-blind maintenance phase, during which dosages of study medication and concomitant antiepileptic drugs were maintained. The primary endpoint was change from baseline to the end of the maintenance phase (week 20) in the Anger-Hostility subscale score of the Profile of Mood States (POMS). RESULTS: Improvement with lamotrigine relative to levetiracetam was observed for mean +/- SD (standard deviation) change from baseline to the end of the maintenance phase (week 20) on the Anger-Hostility subscale (lamotrigine -2.0 +/- 8.2, levetiracetam -0.3 +/- 8.4; p = 0.024) (the primary endpoint); the Anger-Hostility subscale on weeks 5, 6, 7, 8, 9, 11, 12, 14, 16, 18, and 19; and the Total Mood Disturbance score on weeks 6, 7, 8, 9, 11, 12, 17, 19, and 20. Improvement (p < 0.05) with lamotrigine relative to levetiracetam was also observed on the POMS subscales Depression-Dejection, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment. No difference in seizure frequency was observed between groups. The most common adverse events with both medications were headache and dizziness. DISCUSSION: Adjunctive lamotrigine significantly improved Anger-Hostility subscale scores relative to adjunctive levetiracetam in patients with partial seizures at the end of 20 weeks. This difference was consistently observed throughout the treatment period. Similar improvement with lamotrigine versus levetiracetam was observed for other mood symptoms.

Depressive symptoms in epilepsy: prevalence, impact, aetiology, biological correlates and effect of treatment with antiepileptic drugs.

Occurring in up to 80% of patients with epilepsy, depression in epilepsy may manifest as (i) major depressive disorder, meeting Diagnostic and Statistical Manual, 4th edition (DSM-IV) diagnostic criteria; (ii) atypical depression or dysthymia; or (iii) a dysthymic-like disorder with intermittent symptoms that can be milder than those of major depression. Depressive symptoms impair patients' health-related quality of life and may affect the clinical course of epilepsy. Depressive symptoms in epilepsy have been attributed to several causes, including endocrine and/or metabolic effects of seizures; the psychological response to epilepsy and its associated mental, physical and social challenges; common pathogenic mechanisms between depression and epilepsy; and the adverse effects of certain antiepileptic drugs (AEDs), particularly GABAergic agents, such as vigabatrin, tiagabine, topiramate and phenobarbital. Whereas some AEDs impair mood, others appear to improve aspects of mood or are mood neutral. Demonstrable antidepressant efficacy of AEDs used to manage seizures could have a significant impact on the care of patients with epilepsy. The AED lamotrigine has been demonstrated to be effective in the treatment of depressive symptoms in patients with epilepsy. In randomized, double-blind, clinical trials in patients with epilepsy, depressive symptoms improved more with lamotrigine monotherapy than valproate monotherapy and more with lamotrigine adjunctive therapy than placebo. Results of open-label studies of lamotrigine monotherapy and adjunctive therapy are consistent with the results of double-blind clinical trials. Lamotrigine-associated improvement in depressive symptoms is independent of its anticonvulsant efficacy. In prospective assessments, gabapentin, levetiracetam and oxcarbazepine each exhibited potentially beneficial effects on depressive symptoms in patients with epilepsy. However, evidence for the efficacy of gabapentin, levetiracetam and oxcarbazepine in the treatment of depressive symptoms in epilepsy is inconclusive at present because the effects of each agent have only been reported in single studies of an open-label design and with small sample sizes.

Lacosamide for uncontrolled primary generalized tonic-clonic seizures: An open-label pilot study with 59-week extension.

OBJECTIVE: Assess the safety of adjunctive lacosamide for the treatment of uncontrolled primary generalized tonic-clonic seizures in patients (16-65 years) with primary generalized (genetic) epilepsy (PGE). METHODS: An open-label pilot safety study (SP0961; NCT01118949), comprising 12 weeks' historical baseline, 4 weeks' prospective baseline, 3 weeks' titration (target: 400mg/day adjunctive lacosamide) and 6 weeks' maintenance. Patients who continued to the extension study (SP0962; NCT01118962) then received ≤59 weeks of flexible treatment (100-800mg/day lacosamide with flexible dosing of concomitant antiepileptic drugs). The primary outcomes for SP0961 were the mean change (±standard deviation) in absence seizure or myoclonic seizure days per 28days from prospective baseline to maintenance; for SP0962, the incidence of treatment-emergent adverse events (TEAEs) and withdrawals because of TEAEs. RESULTS: Of the 49 patients who enrolled, 40 (82%) completed the pilot study and 9 discontinued (5 because of adverse events). Of the 39 patients who continued to the extension study, 10 discontinued (2 owing to TEAEs) and 29 (74%) completed the study. During the pilot study, patients reported a reduction in mean (±standard deviation) absence and myoclonic seizure days per 28days (-0.37±4.80, -2.19±5.80). Reductions were also observed during the extension study (-2.38±5.54, -2.78±6.43). Five patients in SP0961 and 2 patients in SP0962 experienced TEAEs of new or increased frequency of absence seizures or myoclonic seizures. The most common TEAEs during SP0961 were dizziness (39%) and nausea (27%), and during SP0962 were dizziness (26%) and upper respiratory tract infection (26%). CONCLUSIONS: The safety profile of adjunctive lacosamide was similar to that previously published. Adjunctive lacosamide did not systematically worsen absence or myoclonic seizures, and appears to be well tolerated in patients with PGE.

Lamotrigine therapy in patients requiring a change in antiepileptic drug regimen.

INTRODUCTION: The tolerability of lamotrigine as adjunctive and monotherapy in patients requiring a change in antiepileptic drug (AED) therapy was assessed in this multicenter, open-label study. Open-label studies conducted in the clinic setting may provide additional drug tolerability and effectiveness information that may not be evident in pre-approval clinical trials. METHODS: Adult patients with partial seizures received adjunctive lamotrigine for 16 weeks. Patients taking a single enzyme-inducing AED could convert to lamotrigine monotherapy for an additional 12 weeks. Patients were assessed at baseline, end of adjunctive therapy, and end of monotherapy using the Liverpool Adverse Experience Profile (AEP), Quality of Life in Epilepsy-31, a patient satisfaction rating, and a subjective investigator global assessment. RESULTS: Of the 547 patients enrolled (mean age 42.7 years, 58% female), 421 (77%) completed adjunctive therapy. Upon completion of the adjunctive phase, mean improvement from baseline was 4.3 points on the AEP, and investigators rated 71% of patients as improved in global status. Overall score on the QOLIE 31 improved by 10 points from baseline. One hundred and seventy-eight patients entered and 143 (80%) patients completed the monotherapy phase. In patients completing lamotrigine monotherapy, mean improvement from baseline was 5.9 points on the AEP, and investigators rated 92% as improved in global status. Overall score on the QOLIE 31 score improved by 15 points from baseline. CONCLUSION: Lamotrigine as adjunctive treatment and monotherapy may improve side effect burden and quality of life in patients requiring a change in AED therapy.

Effects of lamotrigine monotherapy in patients with newly diagnosed juvenile myoclonic epilepsy: An open-label study.

BACKGROUND: It is important that drug therapy for juvenile myoclonic epilepsy(JME), a lifelong disorder requiring long-term therapy, is effective and well tolerated with long-term use. Lamotrigine as monotherapy or adjunctive therapy has been demonstrated to be effective in reducing the frequency of partial and generalized seizures in short- and long-term studies in children, adolescents, adults, and elderly patients with epilepsy, including those with JME. With its tolerability profile and spectrum of efficacy, lamotrigine might be an appropriate option for newly diagnosed patients with JME, a possibility that has not been empirically assessed. OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of lamotrigine monotherapy in patients with newly diagnosed JME. METHODS: This open-label study was conducted at 18 clinical sites across the United States. Patients aged ≥12 years with newly diagnosed JME and who had experienced at least 1 generalized motor seizure since diagnosis but were antiepileptic treatment-naive or had received inappropriate treatment due to misdiagnosis were enrolled. During the first 8 weeks of the study, lamotrigine (25-mg or 100-mg tablets) was introduced (to a maximum dosage of 100-500 mg/d, based on instructions in the package insert and clinical response). This dose escalation was followed by a 24-week treatment phase during which lamotrigine dose could be adjusted as needed to achieve optimal clinical benefit. Efficacy end points included the rates of patients with a decrease from baseline of at least 50% in the frequency of myoclonic, tonic-clonic, and absence seizures; and the rate of patients with mild, moderate, or marked improvement from baseline in global clinical status as perceived by the investigators. Adverse events were recorded in patient diaries, and diary information was reviewed by study personnel at clinic visits. Results were analyzed using descriptive statistics. RESULTS: Twenty-nine patients (17 females, 12 males; mean [SD] age, 24.0 [11.3] years [range, 12-50 years]) were included in the efficacy analysis. During the lamotrigine monotherapy treatment period, 58% of patients experienced a reduction from baseline of at least 50% in days with myoclonic seizures, and 56% and 38% of patients experienced a reduction of at least 50% in the frequency of generalized tonic-clonic seizures and absence seizures, respectively. At week 24 of the monotherapy phase, investigators perceived that 72% of patients had shown mild, moderate, or marked improvement in global clinical status relative to the start of the study. CONCLUSIONS: In this study, lamotrigine monotherapy given to patients with newly diagnosed JME was associated with a reduction in the frequency of seizures and improvement in global clinical status as rated by the investigators. Lamotrigine was generally well tolerated.

Is a separate monotherapy indication warranted for antiepileptic drugs?

Antiepileptic drugs (AEDs) are the only neurotherapeutics for which regulatory approval is consistently separated into monotherapy or adjunctive-therapy indications. Because head-to-head comparisons of AEDs (used in the European Union to approve drugs for monotherapy) have not shown substantial differences in efficacy between drugs, FDA approval for use of an AED as monotherapy has typically been based on trials with novel designs that have been criticised for reasons of ethics and clinical relevance. Many new-generation AEDs have not been approved for monotherapy, causing drug labelling and real-world use to be increasingly inconsistent, with negative consequences for patients. The regulatory requirement for separate monotherapy and adjunctive-therapy indications in epilepsy is unnecessarily restrictive. We recommend that regulatory agencies approve AEDs for the treatment of specific seizure types or epilepsy syndromes, irrespective of concomitant drug use.

Time course of lamotrigine de-induction: impact of step-wise withdrawal of carbamazepine or phenytoin.

OBJECTIVE: The objective of the present analysis is to examine lamotrigine (LTG) pharmacokinetics both during polytherapy with enzyme inducing antiepileptic drugs and to evaluate the time course of de-induction following the step-wise withdrawal of enzyme inducers. BACKGROUND: LTG pharmacokinetics can be significantly influenced by concomitant AEDs, and the addition of enzyme inducers can markedly increase LTG clearance, thereby reducing serum concentrations. A clinically relevant question is how will LTG clearance and resulting plasma concentrations be altered during concomitant enzyme inducer withdrawal/conversion process. DESIGN/METHOD: As part of a previously published, active-control, LTG monotherapy trial, dose and plasma concentration data for LTG, carbamazepine (CBZ) or phenytoin (PHT) were obtained. Following the attainment of a LTG target dose of 500 mg/day, CZB or PHT were withdrawn in weekly 20% decrements. Following inducer withdrawal, LTG was then continued as monotherapy for an additional 12 weeks. Plasma concentrations and daily doses of LTG, CBZ, or PHT were obtained at regularly scheduled study visits during inducer withdrawal and during LTG monotherapy. Pharmacokinetic analysis of the plasma concentration data was done to determine the time-course and effect of inducer plasma concentration on LTG oral clearance (Cl(o)), where LTG Cl(o) was estimated as the dose/concentration ratio. RESULTS: Of the 156 patients enrolled in this trial, 76 were assigned to LTG arm, 43 completed the withdrawal to monotherapy phase with 28 successfully completing the study. In a subset analysis of completers, LTG Cl(o) determined prior to withdrawal of the inducers was significantly greater in patients (n=28) on LTG+PHT (160% increase) than in those (n=48) receiving LTG+CBZ (62% increase): 1.77+/-0.77 vs. 1.06+/-0.41 ml/min/kg, respectively, p=0.017. The significant reduction in LTG Cl(o) occurred only when CBZ plasma concentrations reached approximately 2 microg/ml or PHT plasma concentrations reached zero. CONCLUSIONS: Mean LTG plasma concentrations will approximately double following the withdrawal PHT; however increases of only 60% may occur following the withdrawal of CBZ. Importantly, these data suggest that LTG concentrations would not be expected to increase until the concomitant inducer is almost completely removed.

Higher androgens and weight gain with valproate compared with lamotrigine for epilepsy.

BACKGROUND: Valproate is used widely for the treatment of epilepsy but has been associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. The mechanism for these associations is unknown, but they have been hypothesized to be secondary to valproate-associated weight gain. This study was conducted to test the hypothesis that the antiepileptic drug lamotrigine, which also has a broad spectrum of anti-seizure efficacy, would not be associated with endocrine abnormalities and would not cause weight gain. OBJECTIVE AND METHODS: This open-label, cross-sectional study compared (1) endocrine and lipid measures during the early follicular phase of the menstrual cycle; (2) prevalence of menstrual disorders (from patient diaries recorded over three cycles); and (3) body weight of women with epilepsy on lamotrigine monotherapy (n=119) with those on valproate monotherapy (n=103) for <5 years. RESULTS: Mean total serum testosterone and androstenedione levels were higher (P<0.02) in the valproate group compared with the lamotrigine group. More lamotrigine patients (87%) than valproate patients (77%) reported regular menstrual cycles at the Screening Visit. The prevalence of anovulation did not differ between lamotrigine and valproate. Mean HDL cholesterol levels were higher (P<0.01) with lamotrigine compared with valproate as were LDL and total cholesterol levels (P<0.05). Mean total insulin levels did not significantly differ between the groups. Whereas mean body weight in lamotrigine patients did not differ between the time lamotrigine treatment was initiated and the Study Visit, mean weight in valproate patients increased by 3.7 kg. CONCLUSIONS: Compared with lamotrigine monotherapy, valproate monotherapy was associated with weight gain and higher androgen levels in women with epilepsy. These data suggest that the hyperandrogenism observed in some women using valproate for epilepsy may be secondary to drug therapy. Lamotrigine monotherapy may be more appropriate than valproate for women in whom reproductive endocrine or metabolic abnormalities are potential concerns, i.e. women with concerns about weight gain, diabetes, hirsutism, polycystic ovary syndrome, menstrual dysfunction or infertility.

Efficacy and safety of lamotrigine in pediatric patients.

Accumulating data suggest that lamotrigine, which has been available for adult use in epilepsy for more than a decade in clinical practice, also confers effective, well-tolerated control of a range of childhood epilepsies. Lamotrigine is currently approved for the treatment of epilepsy by regulatory authorities in 93 countries, more than 70 of which have approved its use in pediatric patients on the basis of data from well-controlled clinical trials. The controlled clinical trials data have been supplemented over the years by clinical practice data, primarily from uncontrolled studies, confirming or demonstrating additional efficacy of lamotrigine for a range of seizure types. This article reviews the data from well-controlled clinical trials and studies conducted in clinical practice to present an updated perspective on the efficacy and safety of lamotrigine in pediatric patients.

Long-term tolerability and efficacy of lamotrigine in pediatric patients with epilepsy.

Accumulating data suggest that the antiepilepsy drug lamotrigine, which has been available for adult use for more than a decade, also confers broad-spectrum, well-tolerated control of epilepsy in children. The current study--the open-label continuation phase of several short-term clinical trials--was conducted to assess the long-term tolerability and efficacy of lamotrigine as open-label adjunctive therapy or monotherapy in pediatric patients for a variety of seizure types and syndromes including partial seizures, absence seizures, and Lennox-Gastaut syndrome. Clinic visits occurred every 24 weeks throughout the treatment period. A total of 252 patients under 16 years of age were enrolled in the study. The numbers of patients exposed to at least 48 weeks, 96 weeks, and 144 weeks of treatment with lamotrigine were 185 (73.4%), 119 (47.2%), and 60 (23.8%), respectively, for an average duration of exposure of 96.7 weeks. The most common adverse events considered by the investigator to be drug related were dizziness (9.1%), somnolence (7.9%), nausea (6.3%), vomiting (5.2%), and headache (5.2%). The most common serious adverse events (regardless of suspected cause) included pneumonia (3.0%) and infection (1.9%). Investigators judged that the overall clinical status of three-fourths of the patients had improved at treatment weeks 48 and 96 relative to prelamotrigine clinical status. Lamotrigine administered as monotherapy or adjunctive therapy for an average of 2 years (96.7 weeks) was well tolerated and effective in pediatric patients with partial or generalized epilepsy. These results complement and extend the large body of data demonstrating the tolerability and efficacy of lamotrigine with short- and long-term use in adults.

Lamotrigine extended-release as adjunctive therapy with optional conversion to monotherapy in older adults with epilepsy.

PURPOSE: To determine the tolerability and efficacy of lamotrigine extended-release (LTG XR) as adjunctive therapy with optional conversion to monotherapy in patients ages≥65 years with epilepsy. METHODS: This open-label study included the standard LTG XR dose escalation, an 8-week Adjunctive Maintenance Phase (AMP), a 13-week Adjunctive Optimization Phase or Conversion and Monotherapy Phase, and a Taper/Follow-Up Phase. At the end of the AMP, patients on a single concomitant antiepileptic drug (AED) were converted to LTG XR monotherapy over 5 weeks and then remained in the Monotherapy Maintenance Phase for 8 weeks. All other patients remained in the study on concomitant AEDs for an additional 13 weeks in the Adjunctive Optimization Phase. KEY FINDINGS: The number of patients who took ≥1 dose of study medication was 121. Of the 92 patients completing the AMP, 68 patients (74%) were deemed by their treating physician to be eligible to proceed with monotherapy; the remaining 24 patients (26%) continued in the Adjunctive Optimization Phase. The types of adverse events reported with LTG XR were similar to those in studies of LTG XR in younger adult patients with epilepsy and studies of LTG immediate-release (IR) across age groups with epilepsy. No serious rashes were reported. For subjects who were not seizure free at baseline (n=55), the median baseline seizure frequency was 0.5 seizures per week. During the entire treatment period, the median percent change from baseline was 90% (p<0.0001). Fifty-two (52) patients (76%) of the 68 who entered the monotherapy phase successfully converted to monotherapy. SIGNIFICANCE: In this small open label study, LTG-XR was safe and effective when added to the AED regimen of older patients with epilepsy. Many patients were able to be converted to LTG-XR monotherapy.

Long-term tolerability and safety of lamotrigine extended-release: pooled analysis of three clinical trials.

BACKGROUND: In three randomized double-blind clinical trials, lamotrigine extended-release (lamotrigine XR) was demonstrated to be effective in the adjunctive treatment of intractable partial seizures or primary generalized tonic-clonic seizures and as monotherapy for partial seizures. OBJECTIVE: A pooled analysis of the data from these three clinical trials was performed to determine whether the tolerability and safety profile of lamotrigine XR was similar to lamotrigine immediate-release (lamotrigine IR). METHODS: This report describes results of a pooled analysis of the tolerability and safety data from the double-blind and open-label phases of these three trials. The number of patients in the integrated database exposed to one or more doses of lamotrigine XR was 662. RESULTS: Duration of exposure to lamotrigine XR was ≥26 weeks in 82.5 % of patients and ≥52 weeks in 40.8 % of patients [mean (standard deviation) 39.8 (23.3) weeks]. The number of patients with one or more adverse events during double-blind or open-label treatment was 455 (69 %). The most common treatment-emergent adverse events, regardless of suspected cause, were headache (25 % of patients) and dizziness (16 % of patients). The number of patients with one or more adverse events considered to be reasonably attributed to lamotrigine XR during double-blind or open-label treatment was 202 (31 %). The most common adverse events considered to be reasonably attributed to lamotrigine XR were dizziness (10 % of patients) and headache (6 % of patients). Lamotrigine-attributed rash was reported in 4 % of patients and was the reason for premature withdrawal in 2 %. Adverse events leading to premature withdrawal were reported in 7 % of patients. The incidence of serious lamotrigine-attributed adverse events was 1 %. One case of serious rash was reported. No cases of rash were reported to be Stevens-Johnson syndrome or toxic epidermal necrolysis. Two deaths (acute cardiac failure and acute lamotrigine poisoning) were considered reasonably attributable to lamotrigine XR. No evidence of lamotrigine-attributed changes was observed in clinical laboratory data or vital signs. CONCLUSION: The results show that lamotrigine XR is well tolerated with safety and tolerability profiles similar to those of lamotrigine IR. Given the similar safety, tolerability and efficacy profiles of lamotrigine XR and lamotrigine IR, the extended-release formulation may be preferable for many patients because of its ease of use (with once-daily dosing regardless of concomitant antiepileptic drug), the potential for enhanced compliance with once-daily dosing, and the provision of more stable serum drug concentrations. The benefit of once-daily dosing must be balanced with the potentially greater negative impact of a missed dose.

Analysis of three lamotrigine extended-release clinical trials: comparison of pragmatic ITT and LOCF methodologies.

Early withdrawal of patients from a clinical trial can compromise the robustness of the data by introducing bias into the analysis. This is most commonly addressed by using the "intent to treat" (ITT) population and "last observation carried forward" (LOCF) methodology, where a patient's last assessment is carried forward. This can lead to overstatement of treatment efficacy especially if events indicative of treatment failure are infrequent. An alternative methodology, labeled "pragmatic ITT" (P-ITT), requires patients to have a positive outcome and to complete the trial in order to be considered a treatment success by that outcome measure. Data from 3 randomized multicenter lamotrigine extended-release (LTG XR) trials were analyzed and response (proportions seizure-free and with 50% response) were compared using LOCF and P-ITT methodologies. In 2 of the 3 trials, a lower response for both seizure freedom and 50% response was seen during the Maintenance phase using the P-ITT methodology. In the trial that did not show a difference, only a small number of patients withdrew early, thus negating the benefit brought by the P-ITT method. Differences between methodologies were not noted when evaluation was applied to the entire treatment period, most likely a reflection of the fact that a therapeutic dose of lamotrigine is not rapidly achieved. We propose that the P-ITT may be a simpler, more informative method for evaluating the effectiveness of a drug, especially in comparison to another active drug(s).

Lamotrigine XR conversion to monotherapy: first study using a historical control group.

The efficacy and safety of lamotrigine extended-release tablets (LTG XR) as monotherapy for partial seizures were evaluated using the conversion-to-monotherapy design, and historical data as the control. This methodology was recently approved by the United States Food and Drug Administration, and this study is the first historical control design in epilepsy to complete enrollment. Patients ≥13 years old with uncontrolled partial epilepsy receiving monotherapy with valproate or a noninducing antiepileptic drug were converted to once-daily LTG XR (250 mg or 300 mg) as monotherapy and were followed up for 12 additional weeks. Efficacy was measured by the proportion of patients meeting predefined escape criteria for seizure worsening compared with aggregated pseudoplacebo control data from 8 previously conducted conversion-to-monotherapy trials. Nonoverlap of the 95% confidence limit for LTG XR and the 95% prediction interval of the historical control denotes efficacy. Of 226 randomized patients, 174 (93 in 300 mg/day group and 81 in 250 mg/day group) started withdrawal of the background AED and were evaluated for escape. In the historical control analysis population, the lower 95% prediction interval of the historical control (65.3%) was not overlapped by the upper 95% confidence limit of either LTG XR (300 mg/day; 37.2%) or LTG XR (250 mg/day; 43.4%). Adverse events were reported in 53% and 61% of patients receiving LTG XR (300 mg/day and 250 mg/day, respectively). LTG XR (250 mg or 300 mg once daily) is effective for conversion-to-monotherapy treatment of partial seizures in patients ≥13 years old.