Efficacy and safety of belimumab in paediatric and adult patients with systemic lupus erythematosus: an across-study comparison.

OBJECTIVE: To assess the efficacy and safety of belimumab in paediatric versus adult patients with systemic lupus erythematosus (SLE). METHODS: We performed across-study comparisons of patients with active SLE who received belimumab or placebo, plus standard therapy, in PLUTO (paediatric phase II) and BLISS-52, BLISS-76, BLISS-NEA and EMBRACE (adult phase III). Analysed efficacy data included Week 52 SLE Responder Index (SRI)-4 response rate (EMBRACE: SRI with modified Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) proteinuria scoring (SRI-S2K)); SRI-4 response rate (EMBRACE: SRI-S2K) according to baseline disease activity indicators (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score; anti-dsDNA/C3/C4 levels); Week 52 SRI-6 response rate; and time to first severe flare (SELENA-SLEDAI Flare Index) over 52 weeks. Safety data were compared for all aforementioned studies along with adult LBSL02 (phase II) and BLISS-SC (phase III). RESULTS: SRI-4 response rates were similar across the paediatric and adult studies; more belimumab-treated patients achieved SRI-4 responses versus placebo (PLUTO: 52.8% vs 43.6%; BLISS-52: 57.6% vs 43.6%; BLISS-76: 43.2% vs 33.8%; BLISS-NEA: 53.8% vs 40.1%; EMBRACE: 48.7% vs 41.6%). Across all studies, SRI-4 response rates were generally greater in patients with baseline SELENA-SLEDAI scores ≥10 than in patients with baseline SELENA-SLEDAI scores ≤9. A similar proportion of belimumab-treated patients achieved SRI-6 across all studies (PLUTO: 41.2%; BLISS-52: 46.2%; BLISS-76: 33.1%; BLISS-NEA: 43.9%; EMBRACE: 37.5%). Belimumab reduced the risk of severe flare versus placebo in all studies. The incidence of adverse events was similar across all studies. CONCLUSIONS: These analyses demonstrate consistent efficacy and safety of belimumab plus standard therapy across paediatric and adult patients with SLE. TRIAL REGISTRATION NUMBERS: PLUTO (NCT01649765); BLISS-52 (NCT00424476); BLISS-76 (NCT00410384); BLISS-NEA (NCT01345253); EMBRACE (NCT01632241); BLISS-SC (NCT01484496); and LBSL02 (NCT00071487).

Efficacy and Safety of Subcutaneous Belimumab in Systemic Lupus Erythematosus: A Fifty-Two-Week Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: To assess the efficacy and safety of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE). METHODS: Patients with moderate-to-severe SLE (score of ≥8 on the Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] version of the SLE Disease Activity Index [SLEDAI]) were randomized 2:1 to receive weekly SC belimumab 200 mg or placebo by prefilled syringe in addition to standard SLE therapy for 52 weeks. The primary end point was the SLE Responder Index (SRI4) at week 52. Secondary end points were reduction in the corticosteroid dosage and time to severe flare. Safety was assessed according to the adverse events (AEs) reported and the laboratory test results. RESULTS: Of 839 patients randomized, 836 (556 in the belimumab group and 280 in the placebo group) received treatment. A total of 159 patients withdrew before the end of the study. At entry, mean SELENA-SLEDAI scores were 10.5 in the belimumab group and 10.3 in the placebo group. More patients who received belimumab were SRI4 responders than those who received placebo (61.4% versus 48.4%; odds ratio [OR] 1.68 [95% confidence interval (95% CI) 1.25-2.25]; P = 0.0006). In the belimumab group, both time to and risk of severe flare were improved (median 171.0 days versus 118.0 days; hazard ratio 0.51 [95% CI 0.35-0.74]; P = 0.0004), and more patients were able to reduce their corticosteroid dosage by ≥25% (to ≤7.5 mg/day) during weeks 40-52 (18.2% versus 11.9%; OR 1.65 [95% CI 0.95-2.84]; P = 0.0732), compared with placebo. AE incidence was comparable between treatment groups; serious AEs were reported by 10.8% of patients taking belimumab and 15.7% of those taking placebo. A worsening of IgG hypoglobulinemia by ≥2 grades occurred in 0.9% of patients taking belimumab and 1.4% of those taking placebo. CONCLUSION: In patients with moderate-to-severe SLE, weekly SC doses of belimumab 200 mg plus standard SLE therapy significantly improved their SRI4 response, decreased severe disease flares as compared with placebo, and had a safety profile similar to placebo plus standard SLE therapy.

Evaluation of a novel autoinjector for subcutaneous self-administration of belimumab in systemic lupus erythematosus
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OBJECTIVE: To study self-administration and pharmacokinetics (PK) of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE). METHODS: Patients previously treated with belimumab self-administered belimumab 200 mg SC weekly for 8 weeks using an autoinjector. The primary endpoint was the proportion of patients able to self-administer their first and second dose (weeks 1 and 2) in the clinic. The proportion able to self-administer at weeks 4 and 8 (clinic) and weeks 3, 5, 6, and 7 (home) were secondary endpoints. Belimumab PK, safety, and injection-site pain were assessed. RESULTS: 91/95 patients completed the study (withdrawals: adverse events (AEs): 3; lost to follow-up: 1). 93% were female, and mean (SD) age was 44.8 (12.50) years. The majority (99%, 89/90; no attempt, n = 5) successfully self-administered belimumab SC at weeks 1 and 2 (5 had clinic staff assistance), and 98% (85/87) successfully self-administered at weeks 4 and 8. Home-administration success rates were high (93%, (81/87) at weeks 3, 5, 6, and 7). Week 8 median trough concentration was 113 µg/mL. For patients with a ≤ 1.5-week interval between IV SC administration, week-1 concentrations were higher vs. week 8 (+ 51% median) but within a range observed with IV dosing; those with a ≥ 2.5-week interval had median differences close to 0. AEs and serious AEs were low, with no deaths; pain levels were low and decreased with subsequent injections. CONCLUSION: Patients with SLE successfully self-administered belimumab SC using a novel autoinjector; the PK profile was stable following a switch from IV with acceptable AE and pain levels. The recommended dosing interval between IV to SC dosing is 1 - 4 weeks.
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Cumulative Corticosteroid Dose Over Fifty-Two Weeks in Patients With Systemic Lupus Erythematosus: Pooled Analyses From the Phase III Belimumab Trials.

OBJECTIVE: To examine the effects of treatment with belimumab on corticosteroid dose in patients with systemic lupus erythematosus (SLE) over 52 weeks in 2 randomized, controlled trials. METHODS: Data on patients who were taking corticosteroids at baseline in the Study of Belimumab in Subjects with SLE trials were pooled post hoc to compare patients who received belimumab 10 mg/kg plus standard therapy with those who received placebo plus standard therapy. The primary end point was cumulative change from baseline in corticosteroid dose (prednisone equivalent) through week 52. Further analyses specifically examined oral corticosteroid dose. RESULTS: At baseline, 966 of 1,125 patients (86%) were receiving corticosteroids (478 belimumab 10 mg/kg and 488 placebo). Most were women (94%), their mean age was 37.1 years, mean Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index score was 9.8, and mean corticosteroid dosage was 12.5 mg/day. Over 52 weeks, there was a smaller increase in mean cumulative corticosteroid dose for the belimumab group than for the placebo group (531.2 mg versus 916.3 mg; P < 0.0001). Compared with placebo, the mean of all decreases in cumulative corticosteroid dose was higher with belimumab (P = 0.0165), and the mean of all increases was lower (P = 0.0005). More patients in the belimumab group had decreases in oral corticosteroid dose (38.5% versus 30.9%), and fewer had increases in dose (18.4% versus 30.7%), compared with placebo. Adverse events were comparable across groups. CONCLUSION: Our findings show a significantly smaller increase in cumulative corticosteroid dose over 1 year, more patients with decreases in oral corticosteroid dose, and fewer patients with increases in oral corticosteroid dose in the belimumab group compared with the placebo group. These data suggest that belimumab may be steroid sparing.

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.

Effects of lamotrigine on mood in older adults with epilepsy and co-morbid depressive symptoms: an open-label, multicentre, prospective study.

BACKGROUND: Both epilepsy and depressive symptoms are more prevalent in older individuals than in any other age group. Furthermore, depressive symptoms are among the most common interictal psychiatric co-morbid disorders in people with epilepsy. For these reasons, pharmacological treatment of epilepsy that might also confer antidepressant effects may be particularly beneficial in older patients. In this respect, lamotrigine is of considerable interest amongst antiepileptic drugs (AEDs) because it has proven thymoleptic activity. OBJECTIVE: These analyses, conducted on a data set drawn from a previously reported, open-label, multicentre, prospective study, examined the effect of lamotrigine on mood in adults aged>or=50 years with epilepsy and co-morbid depressive symptoms. All subjects were receiving background AED therapy at baseline. METHODS: Of the 158 subjects enrolled in the initial study, 40 adults (24 women, 16 men) met the age criterion for these analyses. The study consisted of a screening/baseline phase and four treatment phases over 36 weeks: lamotrigine escalation phase (7 weeks); lamotrigine maintenance or adjunctive therapy phase (12 weeks); concomitant AED withdrawal phase (5 weeks); and lamotrigine monotherapy phase (12 weeks). Psychometric evaluation of mood utilized the Beck Depression Inventory (BDI-II), Center for Epidemiological Studies Depression Scale (CES-D), the Neurological Disorders Depression Inventory in Epilepsy (NDDI-E) and the Profile of Mood States (POMS). Scores at the end of the adjunctive and monotherapy phases were compared with baseline scores. Lower scores on these scales indicate less depressive symptomatology. RESULTS: Mean baseline scores for the BDI-II, CES-D, NDDI-E and POMS were 15.8, 24.3, 13.8 and 57.7, respectively. Change scores were statistically significant (p<0.01) compared with baseline at the end of the adjunctive and monotherapy phases for all four psychometric measures of mood, with the exceptions of BDI-II and NDDI-E at the end of the adjunctive phase. CONCLUSIONS: The older adults in these analyses presented with low to moderate levels of depressive symptoms. Addition of lamotrigine to background AED therapy demonstrated antidepressant activity similar to that for the whole sample in the initial study. Given that the onset and prevalence of epilepsy are higher in older adults than in any other age group, pharmacological treatment for epilepsy in older patients that might also confer antidepressant therapy may be particularly beneficial.

Lamotrigine monotherapy for newly diagnosed typical absence seizures in children.

PURPOSE: To evaluate the efficacy, tolerability, and effects on behavior and psychosocial functioning of lamotrigine monotherapy in children with newly diagnosed typical absence seizures. PATIENTS AND METHODS: Children meeting enrollment criteria (n=54) received a confirmatory 24-h ambulatory electroencephalogram (EEG) and then entered a Escalation Phase of up to 20-weeks during which lamotrigine was titrated until seizures were controlled or maximum dose (10.2mg/kg) was reached. Seizure freedom was assessed by diary review and clinic hyperventilation (clinic HV) and then confirmed by EEG with hyperventilation (HV/EEG). Patients who maintained seizure freedom for two consecutive weekly visits were entered into the Maintenance Phase (n=30). Diary, clinic HV, and HV/EEG data were supplemented with 24-h ambulatory EEG at baseline and the ends of the Escalation and Maintenance Phases. Health outcome assessments were completed at screening and at the end of the Maintenance Phase. RESULTS: By the end of the Escalation Phase, seizure-free rates (responders) were 59% by seizure diary (n=51), 56% by HV/EEG (n=54) (primary endpoint), and 49% by 24-h ambulatory EEG (n=49). During the Maintenance Phase, 89% (week 24) and 86% (week 32) remained seizure free by diary (n=28), 78% by clinic HV (n=27), and 81% by 24-h ambulatory EEG (n=26). Seizure freedom was first observed beginning at the fifth week of the Escalation Phase. The most frequent adverse events were headache and cough. Health outcome scores were either improved or unchanged at the end of the Maintenance Phase. CONCLUSIONS: Lamotrigine monotherapy results in complete seizure freedom in a substantial number of children with typical absence seizures. Lamotrigine was well tolerated in this study.

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.

Relative influences of adjunctive topiramate and adjunctive lamotrigine on scanning and the effective field of view.

A subsample of 67 adult patients with partial seizures participating in a randomized, double-blind study comparing the cognitive effects of adjunctive lamotrigine (LTG) and adjunctive topiramate (TPM) was administered Performance On-Line (POL) in addition to a battery of neuropsychological tests at baseline, week 8 and week 16 of treatment. The POL is a self-administered computer task that measures scanning, divided-attention, and the effective field of view. Although the POL does not measure driving performance, POL scores are correlated with driving performance. The results show that adjunctive TPM, but not adjunctive LTG, negatively impacted cognition. Both simple target identification and divided-attention performance on POL were compromised in the TPM group but not in the LTG group. The relative POL impairment associated with chronic TPM treatment was similar to that observed with the acute effects of alcohol with a breath level of .045% or a low dose of alprazolam (0.5mg). Thus, driving-related visual and cognitive skills were compromised by adjunctive TPM treatment. Therapeutic doses of adjunctive TPM pose a potential risk of impaired scanning and divided-attention skills.

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.

Assessment of tolerability in elderly patients: changing to lamotrigine therapy.

BACKGROUND: Of all age groups, adults older than 75 years have the highest risk of seizures, especially partial seizures. In the past, physicians commonly used phenytoin, carbamazepine, and valproic acid as antiepileptic drugs (AEDs) in the elderly. However, these AEDs have potential adverse effects and drug interactions that may make them less desirable than newer AEDs for this age group. OBJECTIVES: The primary objective of this study was to assess the effects of changing the AED regimen to lamotrigine (LTG) in elderly patients (aged >or=60 years) who were initially unsatisfied with their drug regimen because of adverse effects or continuing seizures. These patients comprised a subgroup from a multicenter, open-label trial of partial-seizure patients who switched to LTG. Other objectives included assessing the change in quality of life in patients taking LTG as adjunctive therapy and as monotherapy, and evaluating the efficacy of LTG for seizures when used as adjunctive treatment and as monotherapy. METHODS: The study involved 2 phases: LTG was first added to the regimen, and then patients could change to LTG monotherapy. Tolerability, the primary end point, was assessed using the Liverpool Adverse Experience Profile (AEP). Secondary end points included quality of life, as measured with the Quality of Life in Epilepsy-31 inventory, investigator global assessment, patient's self-rated satisfaction with treatment, and Profile of Mood States. The proportion of patients who completed each phase with at least a 50% reduction in seizures from baseline and the proportion of patients remaining seizure free throughout each phase were also determined. RESULTS: Sixty-two patients aged >or=60 years (mean [SD]age, 71.3 [7.6] years; 31 men, 31 women) were enrolled. After adding LTG, older patients reported fewer adverse effects, improved mood, better quality of life, and fewer seizures. Changing to LTG as monotherapy produced further improvement in all measurements. For the primary end point, mean improvement in AEP scores from baseline was 2.3 at the end of the adjunctive therapy phase (P = 0.027) and 5.7 by the end of the monotherapy phase (P < 0.005). In addition, there was a mean improvement of 2.0 in the AEP score from the adjunctive therapy to the monotherapy phase. CONCLUSIONS: For older patients with seizures who were unhappy with their AED regimen because of adverse effects, continuing seizures, or both, adding LTG to the drug regimen was associated with improved tolerability and effectiveness, and switching to LTG monotherapy was associated with further improvement.

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.

Double-blind, placebo-controlled trial of lamotrigine in combination with other medications for neuropathic pain.

This randomized, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and tolerability of lamotrigine added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic in patients whose neuropathic pain was inadequately controlled with these medications. Patients with neuropathic pain from diabetic peripheral neuropathy, postherpetic neuralgia, traumatic/surgical nerve injury, incomplete spinal cord injury, trigeminal neuralgia, multiple sclerosis, or HIV-associated peripheral neuropathy, who had a mean weekly pain score > or =4 on an 11-point numerical rating scale, were randomized to receive a flexible dose of lamotrigine 200, 300, or 400mg daily (n=111) or placebo (n=109) for up to 14 weeks (including eight weeks of dose escalation) in addition to their prestudy regimen of gabapentin, a tricyclic antidepressant, or a nonopioid analgesic. No statistically significant difference in the mean change in pain-intensity score from baseline to Week 14 (primary endpoint) was detected between lamotrigine and placebo (P=0.67). Differences between lamotrigine and placebo were not statistically significant for secondary efficacy assessments, including mean changes from baseline in the Short-Form McGill Pain Questionnaire, the Neuropathic Pain Scale, rescue medication use, and the percentages of patients rated as much improved or very much improved at the end of treatment on the Clinician Global Impression of Change scale and the Patient Global Impression of Change scale. Lamotrigine was generally well tolerated. Lamotrigine (up to 400 mg/day) added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic did not demonstrate efficacy as an adjunctive treatment of neuropathic pain but was generally safe and well tolerated.

Effect of lamotrigine on depressive symptoms in adult patients with epilepsy.

In this investigation, the effects of lamotrigine versus placebo on depressive symptoms in patients with epilepsy were prospectively assessed. This investigation was a secondary analysis of a randomized, double-blind, placebo-controlled, parallel-group study in which adult patients received adjunctive lamotrigine (n=32) or placebo (n=38) for a 7-week dose escalation phase, followed by a 12-week maintenance phase, for primary generalized tonic-clonic (PGTC) seizures. Mood symptoms were assessed with the Beck Depression Inventory, second edition (BDI-II), the Profile of Mood States (POMS), and the Cornell Dysthymia Rating Scale-Self-Report (CDRS). Mean (SD) BDI-II scores at screening reflected mild depressive symptoms and were similar between groups (lamotrigine 18.3 (12.1), placebo 16.8 (12.0)). At the end of the maintenance phase, mean (SD) improvement from baseline was greater with lamotrigine than placebo with respect to BDI-II score (lamotrigine 8.9 (7.6), placebo 1.7 (8.5), P=0.01) and POMS total score (lamotrigine 32.0 (30.4), placebo 6.5 (32.3), P=0.03) and numerically greater with lamotrigine than placebo for CDRS score (lamotrigine 7.3 (7.8), placebo 4.1 (13.9), P=0.50). Among the subset of patients with at least mild depression (BDI-II score10), mean improvement from baseline was numerically, but not statistically significantly, greater with lamotrigine (11.5, n=13) than placebo (3.1, n=18) (P=0.054). Median percentage reductions in seizure frequency were significantly greater with lamotrigine than placebo during the escalation phase, the maintenance phase, and the escalation and maintenance phases combined for PGTC seizures and all generalized seizures. However, improvement in seizure frequency was not correlated with improvement in mood (r=0.1, P=ns). Compared with placebo, lamotrigine improved mood symptoms independently of seizure reduction in patients with generalized seizures. Lamotrigine may be useful in treating patients with epilepsy and comorbid depressive symptoms.

Lamotrigine in patients with epilepsy and comorbid depressive symptoms.

PURPOSE: This open-label study evaluated the antidepressant qualities of lamotrigine (LTG) in people with epilepsy. METHODS: Eligible patients exhibited low to moderate depressive symptoms and required a change in antiepileptic drug (AED) therapy, but were excluded if they had a major depressive disorder (MDD). Lamotrigine was added onto a stable AED regimen, and self-report instruments were administered to evaluate changes in mood states. Evaluations were conducted at baseline, at the end of 19 weeks of adjunctive treatment, and 36 weeks following conversion to monotherapy. RESULTS: One hundred and fifty-eight patients with epilepsy participated; 96 patients completed adjunctive treatment, and 66 patients completed monotherapy. Intent-to-treat analyses for all instruments showed improvement in depression scores after adjunctive LTG treatment. Improvement was maintained for those converted to monotherapy. CONCLUSIONS: These data suggest that LTG may have antidepressant activity for patients with epilepsy and comorbid low to moderate depressive symptoms, and warrant a randomized controlled trial for validation.

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.