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).

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.

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.

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.

Long-term tolerability and efficacy of lamotrigine in infants 1 to 24 months old.

This open-label study was designed to evaluate the long-term tolerability and efficacy of lamotrigine in 1- to 24-month-old infants with partial seizures. The study enrolled both lamotrigine-naïve patients and patients who had been previously exposed to lamotrigine in a randomized, double-blind, placebo-controlled study. Patients (n = 204) received lamotrigine according to a dosing schedule that depended on prior experience with lamotrigine and concurrent antiepileptic drug therapy for up to 48 weeks or their second birthday, whichever occurred last. Total duration of lamotrigine exposure (which included exposure during the placebo-controlled study in lamotrigine-experienced patients) was >/=24 weeks in 92% of patients, >/=48 weeks in 70% of patients, and >/=72 weeks in 20% of patients. A total of 20 (10%) patients (8 lamotrigine-naïve patients and 12 lamotrigine-experienced patients) transitioned to lamotrigine monotherapy. The most common adverse events were pyrexia (45% of patients), upper-respiratory tract infection (28%), and ear infection (22%). The only adverse event considered reasonably attributable to study medication in >2% of patients was irritability (n = 10; 5% of patients). No cases of serious rash were reported. The median percent reduction from baseline in partial seizure frequency in the sample as a whole was 74%. Seizure frequency was reduced by >/=50% from pre-lamotrigine baseline in 62% of patients in the sample as a whole, 60% of the lamotrigine-naïve subgroup, and 63% of the lamotrigine-experienced subgroup. In the sample as a whole, 13% of patients were seizure free during the Treatment Phase. Investigators considered clinical status at the last clinic visit to be improved (mildly, moderately, or markedly) relative to prelamotrigine clinical status in 76% of patients (150/197) and to be unchanged in 19% (37/197). In this study-the first large prospective investigation of the long-term tolerability and efficacy of an antiepileptic drug in a patient population 2 years and younger-lamotrigine administered for up to approximately 72 weeks was well tolerated and associated with good seizure control.

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.

Steady-state pharmacokinetics of lamotrigine when converting from a twice-daily immediate-release to a once-daily extended-release formulation in subjects with epilepsy (The COMPASS Study).

PURPOSE: To compare the pharmacokinetics (PK) of lamotrigine (LTG) when converting from twice-daily immediate-release (LTG-IR) to once-daily extended-release (LTG-XR) in subjects with epilepsy. METHODS: An open-label, conversion study was conducted, consisting of a 2-week LTG-IR Baseline Phase, followed by a 2-week LTG-XR Treatment Phase and a 1-week LTG-IR Phase. Forty-four subjects (> or =13 years of age) were enrolled and grouped as metabolically neutral (15), induced (15), or inhibited (14) based on the effects of the concomitant antiepileptic drugs (AEDs) on the clearance of LTG. The primary outcome was LTG PK parameters upon conversion. Secondary outcomes included seizure frequency, adverse events, and subject's preference. RESULTS: LTG-XR and LTG-IR regimens were similar with respect to area under curve from 0 to 24 h (AUC (0-24)), apart from the induced group, where the AUC (0-24) of LTG-XR was on average 21% lower than for LTG-IR. A reduction in the LTG Cmax was observed for LTG-XR compared to LTG-IR resulting in a decrease in the peak-to-trough fluctuation in serum LTG concentrations. The steady-state, dose-normalized, trough concentrations for LTG-XR were similar to those of LTG-IR. The median time to peak concentration (Tmax) following administration of LTG-XR ranged from 4 to 6 h, 6 to 10 h, and 9 to 11 h in the induced, neutral, and inhibited groups, respectively. In comparison, the median Tmax following administration of LTG-IR was between 1 and 1.5 h. CONCLUSIONS: Trough concentrations of LTG can be maintained on conversion from twice-daily LTG-IR to once-daily LTG-XR at the same total daily dose.

Conversion to lamotrigine monotherapy from valproate monotherapy in older adolescent patients with epilepsy.

BACKGROUND: Pharmacokinetic interactions can make necessary anti-epileptic medication (AED) changes hazardous for children with epilepsy. We report the utility of a dosing algorithm designed to maintain stable trough lamotrigine (LTG) concentrations during conversion from valproate (VPA) to LTG monotherapy in adolescents aged 16-20 years. METHODS: Patients were enrolled into the study if they required a change in their AED regimen due to lack of efficacy or intolerable side effects. Conversion to LTG monotherapy took place in a four part treatment algorithm. Lamotrigine was escalated according to a target dose of 200 mg/day over 8-weeks. Valproate was withdrawn over a period of 2-6 weeks, depending on the initial dose. Lamotrigine dose was further escalated to 500 mg/day and continued for four weeks as mono therapy. Trough serum concentrations of LTG were measured during each phase of the trial. RESULTS: Twelve of 16 patients completed the study. After the LTG escalation to 200 mg/day, mean trough serum concentrations of 8.0 microg/mL did not differ significantly from the 9.5 microg/mL after VPA withdrawal or the 9.2 microg/mL after 4 weeks of monotherapy at 500 mg/day. Adverse events led to premature discontinuation for one subject. Two subjects withdrew due to worsening seizures during LTG monotherapy possibly due to non-compliance. Limitations of the trial include the open label design and small sample size of the sub-analysis. CONCLUSION: In adolescent patients, this algorithm produces stable LTG serum concentrations with favorable tolerability during a transition from VPA to LTG mono therapy.

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.

Epilepsy and medication effects on the pattern visual evoked potential.

Visual disruption in patients diagnosed with epilepsy may be attributable to either the disease itself or to the anti-epileptic drugs prescribed to control the seizures. Effects on visual function may be due to perturbations of the GABAergic neurotransmitter system, since deficits in GABAergic cortical interneurons have been hypothesized to underlie some forms of epilepsy, some anti-epileptic medications increase cortical GABA levels, and GABAergic neural circuitry plays an important role in mediating the responses of cells in the visual cortex and retina. This paper characterizes the effects of epilepsy and epilepsy medications on the visual evoked response to patterned stimuli. Steady-state visual evoked potentials (VEP) evoked by onset-offset modulation of high-contrast sine-wave stimuli were measured in 24 control and 54 epileptic patients. Comparisons of VEP spectral amplitude as a function of spatial frequency were made between controls, complex partial, and generalized epilepsy groups. The effects of the GABA-active medication valproate were compared to those of carbamezepine. The amplitude of the fundamental (F1) component of the VEP was found to be sensitive to epilepsy type. Test subjects with generalized epilepsy had F1 spatial frequency-amplitude functions with peaks shifted to lower spatial frequencies relative to controls and test subjects with complex partial epilepsy. This shift may be due to reduced intracortical inhibition in the subjects with generalized epilepsy. The second harmonic component (F2) response was sensitive to medication effects. Complex partial epilepsy patients on VPA therapies showed reduced F2 response amplitude across spatial frequencies, consistent with previous findings that showed the F2 response is sensitive to GABA-ergic effects on transient components of the VEP.

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.

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.

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.

Lamotrigine for patients with juvenile myoclonic epilepsy following prior treatment with valproate: results of an open-label study.

This open-label study was designed to evaluate lamotrigine monotherapy as a possible alternative in patients with juvenile myoclonic epilepsy who previously failed treatment with valproate. Patients (n=63) were transitioned from valproate to lamotrigine during an 8-week escalation phase followed by 24 weeks of lamotrigine monotherapy. On Week 24 of the treatment phase, investigators judged that 50 and 67% of patients completing the study had shown mild, moderate, or marked improvement in adverse events and global clinical status, respectively, and 76% of patients rated lamotrigine as somewhat better (13%) or much better (63%) than valproate. The majority of patients completing the study experienced no deterioration of seizure control when switching from valproate to lamotrigine. These results support additional research on lamotrigine in juvenile myoclonic epilepsy.

Efficacy and tolerability of conversion to monotherapy with lamotrigine compared with valproate and carbamazepine in patients with epilepsy.

OBJECTIVE: This randomized, open-label study was designed to compare the efficacy and tolerability of lamotrigine monotherapy with those of valproate and carbamazepine monotherapy in patients with epilepsy whose seizures were uncontrolled on their prestudy antiepileptic drug monotherapy. METHODS: Patients meeting eligibility criteria were randomized 2:1 to lamotrigine:carbamazepine or lamotrigine:valproate. The treatment phase was divided into a 4-week dose-escalation phase (Weeks 1-4), during which lamotrigine, carbamazepine, or valproate was added to patient's prestudy monotherapy; an 8-week add-on phase (Weeks 5-12), during which patients were stabilized on both the study medication and their prestudy antiepileptic therapy; an 8-week withdrawal phase (Weeks 13-20), during which prestudy antiepileptic therapy could be withdrawn if clinically appropriate; and an 8-week monotherapy phase (Weeks 21-28), during which patients could be treated with study medication as monotherapy. RESULTS: The numbers of patients randomized to the carbamazepine and valproate arms of the study were 144 (98 lamotrigine, 46 carbamazepine) and 158 (105 lamotrigine, 53 valproate), respectively. Successful monotherapy sustained for at least 7 weeks was achieved in comparable percentages of patients in the lamotrigine group (56%) and the carbamazepine group (54%) and in more patients in the lamotrigine group (49%) than the valproate group (40%). Among monotherapy completers, the percentage of patients with zero seizures during the monotherapy phase was comparable for lamotrigine (41%) and carbamazepine (30%) and significantly higher (P<0.05) with lamotrigine (32%) than with valproate (11%). No differences between treatments were observed with respect to time to treatment failure or time to first seizure. Lamotrigine was also better tolerated than carbamazepine or valproate. CONCLUSION: Lamotrigine monotherapy was as effective as and better tolerated than carbamazepine or valproate monotherapy in patients whose seizures were uncontrolled on their prestudy antiepileptic drug monotherapy.

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.