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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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).

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.

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.

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.

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.

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.

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.

Efficacy and tolerability of adjunctive lamotrigine for refractory epilepsy in institutional or community residents with mental retardation.

OBJECTIVE: To determine whether the efficacy and tolerability of adjunctive lamotrigine differ as a function of whether persons with mental retardation and refractory epilepsy resided in institutions or the community. RESEARCH DESIGN AND METHODS: The analysis was retrospective and employed data from a previously published, open-label study. To be eligible for enrollment, patients needed to be receiving stable regimens of up to three antiepileptic medications at enrollment and to have experienced at least two seizures per month in the 3 months prior to enrollment. The study included an Escalation Phase during which lamotrigine was titrated to a target dose, an 8-week Maintenance Phase during which doses of lamotrigine and concomitant antiepileptic drugs were maintained, and a 12-week Optimization Phase during which doses of antiepileptic drugs could be adjusted. Outcomes of interest included baseline characteristics; the percentage of persons with 25%, 50%, and 75% reductions in seizure frequency and with zero seizures; investigator-rated clinical status; and mean scores on the Habilitative Improvement Scale and the Aberrant Behavior Checklist. The small sample size did not allow for sufficient power for statistical comparisons between groups. RESULTS: Demographics and baseline clinical characteristics were similar between groups (31 institutional and 36 community residents) except institutional residents were more likely to have severe or profound mental retardation and complex partial and partial secondarily generalized seizures. The percentages of persons with 25%, 50%, and 75% reductions in seizure frequency and zero seizures were 64%, 50%, 29%, and 18% respectively, for community residents and 42%, 38%, 23%, and 12% for institutional residents. Investigator-rated clinical status at the end of the Maintenance Phase was improved versus baseline in 68% of community residents and 62% of institutional residents. Most individuals (81% of institutionalized persons, 69% of community-dwelling persons) were considered to have experienced no change in adverse events with the addition of lamotrigine. The mean Habilitative Improvement Scale score was significantly improved (p < or = 0.05) versus baseline at the end of the Escalation, Maintenance, and Optimization Phases in both groups. CONCLUSION: The efficacy and tolerability of lamotrigine were similar between institutional residents and community residents despite the numerically higher prevalence of severe or profound mental retardation among institutional residents.

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 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.

Lamotrigine monotherapy improves health-related quality of life in epilepsy: a double-blind comparison with valproate.

The effects of monotherapy with lamotrigine on health-related quality of life were compared with those of valproate monotherapy in a randomized, double-blind trial designed to evaluate treatment-emergent weight changes in patients with epilepsy. At the end of 8 months of treatment, significantly more patients using lamotrigine compared with valproate experienced quality-of-life improvements on the Health Perceptions (42% vs 15%), Energy/Fatigue (47% vs 28%), and Social Isolation (35% vs 16%) subscales of the Quality of Life in Epilepsy-89 (QOLIE-89) questionnaire (P<0.05). Compared with valproate-treated patients, lamotrigine-treated patients were four times more likely to experience improvement in Health Perceptions, 2.3 times more likely to experience improvement in Energy/Fatigue, and 2.8 times more likely to experience improvement in Social Isolation (P<0.05). These quality-of-life improvements are consistent with the improvements in mood measured with the Beck Depression Inventory, the Cornell Dysthymia Rating Scale, and the Profile of Mood States among patients receiving lamotrigine. These data show that lamotrigine monotherapy provides benefits over valproate monotherapy in improving several aspects of health-related quality of life in patients with epilepsy. The observation that quality-of-life improvements during lamotrigine monotherapy occurred concurrently with improvements in mood suggests that the quality-of-life and mood changes may be causally related.

Lamotrigine Monotherapy Improves Depressive Symptoms in Epilepsy: A Double-Blind Comparison with Valproate.

Depressive symptoms are highly prevalent in patients with epilepsy. The antiepileptic drug lamotrigine has been shown to be an effective treatment for the depressive phase of bipolar disorder and to enhance mood and well-being in epilepsy patients. The effects of lamotrigine monotherapy on depressive symptoms in epilepsy have not been evaluated to date in a controlled clinical trial. A recently completed double-blind epilepsy trial comparing the effects of lamotrigine monotherapy and valproate monotherapy on weight change incorporated a battery of standard mood assessments. Mean screening Beck Depression Inventory scores showed that both lamotrigine and valproate groups suffered from mild depression at baseline. Lamotrigine monotherapy was reliably associated with earlier and larger improvements than valproate in mood assessed with the Beck Depression Inventory, the Cornell Dysthymia Rating Scale, and the Profile of Mood States. Considered in the context of other data showing lamotrigine's antidepressant efficacy in bipolar depression, these results suggest that lamotrigine improves mood in mildly depressed patients with epilepsy. Lamotrigine may be particularly useful in treating epilepsy patients with comorbid depression, the most common psychiatric illness in epilepsy.

Lamotrigine versus valproate monotherapy-associated weight change in adolescents with epilepsy: results from a post hoc analysis of a randomized, double-blind clinical trial.

Recent trends toward obesity and associated health risks in children highlight the significance of weight gain as a side effect with certain antiepilepsy drugs. No previous study has prospectively compared, in adolescents, weight effects for two commonly used antiepilepsy drugs. We report results from a post hoc subanalysis of adolescent data from a randomized, double-blind study comparing weight effects of lamotrigine and valproate. Patients were > or = 12 years of age with new-onset partial or generalized seizures who were randomized 1:1 to lamotrigine or valproate. Patients were escalated to a dose range of 100 to 500 mg/day for lamotrigine and 10 to 60 mg/kg/day for valproate based on clinical response, with target doses maintained for 24 weeks. Results are reported for adolescents aged 12 to 20 years. Weight changes during maintenance were higher (P < .05) in valproate (n = 20) patients than in lamotrigine (n = 18) patients, and change in body mass index was higher (P < .05) in valproate patients at the end of the study. At week 32, mean body mass index in the valproate group was above the 85th percentile representing "at risk for overweight." Whereas weight remained stable in adolescents treated with lamotrigine, weight increased in those treated with valproate by week 10 of this study and continued to increase at the end of the study.

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.