Human Safety of Lamotrigine

Summary: The clinical safety of lamotrigine (LTG), assessed in four completed randomized, double-blind, placebo-controlled crossover trials and an interim analysis of 27 12-month open studies, is discussed. LTG was added to existing anti-epileptic drugs (AEDs) of adult patients with refractory epilepsy, using a twice-daily regimen. In the pooled data from the four double-blind studies ( n = 92), the incidence of adverse experiences with LTG and placebo did not differ significantly. Two patients were withdrawn on LTG due to adverse experiences (one rash, one nausea and vomiting). In the open studies (pooled data; n = 572) the most commonly reported adverse experiences were dizziness, diplopia, somnolence, headache, ataxia, and asthenia (10–14% incidence). Forty-nine patients (8.6%) were withdrawn with adverse events, most commonly for rash (2.3%). No patients were withdrawn from any of the studies with physical, neurological, or ECG abnormalities thought attributable to LTG treatment. Laboratory measures, vital signs, and weight did not show any consistent changes of clinical significance, and no significant changes in plasma concentrations of concomitant AEDs after the addition of LTG were observed.     

Clinical Pharmacology of Lamotrigine

Summary: The pharmacokinetics and pharmacodynamics of lamotrigine (LTG), a new antiepileptic drug (AED), were studied in healthy volunteers. In an open dose-escalating study, LTG 240 mg produced peak plasma concentrations of around 3 μg/mg with no significant adverse events. Subsequent pharmacokinetic studies revealed complete oral absorption, first-order kinetics with a mean half-life of approximately 1 day, and elimination mainly as a glucuronide in the urine. Early studies in patients with epilepsy revealed more rapid metabolism when given with enzyme-inducing AEDs and delayed metabolism by valproate. A placebo-controlled, double-blind study compared LTG 120 and 240 mg with phenytoin (PHT) 500 and 1,000 mg, and diazepam (DZP) 10 mg. Visual analogue scales showed sedation after PHT 1,000 mg and DZP 10 mg, but not after LTG. Smooth pursuit eye movements and adaptive tracking were impaired by DZP and PHT 1,000 mg. LTG did not affect these variables. A comparison of LTG 150 and 300 mg and carbamazepine (CBZ) 200, 400, and 600 mg demonstrated impairment of smooth pursuit and saccadic eye movements by CBZ 600 and 400 mg, but not by LTG. Additionally, CBZ 600 mg impaired adaptive tracking and increased body sway and heart rate. These studies have shown LTG to have desirable and predictable pharmacokinetic properties for an AED. Pharmacodynamic effects were absent, suggesting a high therapeutic index.     

Neurochemical and Behavioral Aspects of Lamotrigine

Summary: Lamotrigine (LTG), a new anticonvulsant, chemically unrelated to current antiepileptic drugs (AEDs), resembles phenytoin (PHT) and carbamazepine (CBZ) in ability to block hindlimb extension in both the maximal electroshock test and leptazol-induced seizures. Results indicate that LTG may be of value in both partial and generalized seizures. In in vitro studies, LTG has been shown to inhibit veratrine-evoked release of glutamate when a threshold depolarizing concentration (4 μg/ml) is used, and also inhibits aspartate release when a larger stimulus is given (10 μg/ml). However, LTG does not block potassium-evoked transmitter release. LTG is a less potent inhibitor of the release of γ-aminobutyric acid (GABA), acetylcholine, noradrenaline, and dopamine. LTG blocks the neurotoxicity of kainic acid in vivo, supporting the in vitro findings, and suggests that the anticonvulsant effect of LTG may be due to inhibition of glutamate release. In a test of working memory and phencyclidine (PCP) discrimination studies, LTG had no effect, indicating no sharing of the same PCP-like side effects associated with NMDA receptor blockade. In the gerbil model of global ischemia, high doses of LTG provided protection against damage to the CA1 region of the hippocampus. Analogues of LTG of higher potency to block the release of glutamate may be necessary to ensure protection against ischemic brain damage.     

Controlled Trial of Lamotrigine (Lamictar) for Refractory Partial Seizures

The antiepileptic effect of lamotrigine (LTG) was assessed in a double-blind, placebo-controlled crossover trial in 24 adult patients with refractory partial seizures. LTG or placebo was added to existing antiepileptic drugs (AEDs). The dose of LTG varied from 75 to 400 mg daily. Three patients did not complete the trial. One was withdrawn from the trial with ataxia, tiredness, dyspnea, and diplopia while receiving LTG and died 18 days later of invasive carcinoma involving the liver. A second patient was withdrawn during baseline for contravening admission criteria, and a third received LTG in error during both treatment periods. Twenty-one patients (12 men and 9 women) completed the trial. An analysis of seizure counts in the 12-week treatment period with LTG showed a statistically significant reduction in seizures as compared with placebo for total seizures (p less than 0.002), partial seizures (p less than 0.002), and secondarily generalized seizures (p less than 0.05). The analysis of total seizure days showed a significant reduction during LTG treatment (p less than 0.002). There were no statistically significant changes in plasma concentrations of phenytoin (PHT), carbamazepine (CBZ), primidone (PRM), or phenobarbital (PB) between the two treatment periods. The most common adverse events reported during the trial were diplopia, drowsiness, tiredness, ataxia, and headache, but although these were more frequent during LTG treatment, the differences from placebo were not statistically significant. No hematological or biochemical changes were noted.     

An Overview of the Efficacy and Tolerability of New Antiepileptic Drugs

Summary: To evaluate the efficacy and tolerability of recently developed antiepileptic drugs (AEDs), a systematic review of placebo-controlled, randomized controlled trials (RCTs) of the AEDs as add-on therapy in refractory partial epilepsy was conducted. Two or more RCTs meeting our inclusion criteria were found for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS). The outcome selected for estimation of efficacy was the proportion of patients experiencing a ≥50% reduction in seizure frequency from baseline. Tolerability was estimated on the basis of rates of patient withdrawal from study for any reason. Efficacy and tolerability odds ratios (ORs) and 95% confidence intervals (95% CIs) for each measure were generated for each trial included in the analysis, and overall efficacy and tolerability ORs were calculated for each AED across all trials and drug dosages evaluated. Because 95% CIs for both efficacy and tolerability overlapped for the six drugs, conclusive evidence of between-drug differences in effectiveness or safety were not obtained from the analysis. However, the data suggest that the drug with the highest OR for efficacy (TPM) may be approximately twice as effective as the AED with the lowest OR for efficacy (GBP), and that the treatment that appears to most frequently cause withdrawal (ZNS) may be about four times more likely to do so that the AED with the lowest withdrawal rate (LTG). RCTs comparing newer AEDs with the older standard drugs and with each other are needed to further evaluate their relative utility.     

Clinical Administration of New Antiepileptic Drugs: An Overview of Safety and Efficacy

Summary: Gabapentin, lamotrigine, tiagabine, topira-mate, vigabatrin, and zonisamide are all administered as add-on therapy for treatment of patients with refractory epilepsy. To date, no comparative randomized trials have been performed that could potentially allow an evidence-based choice to be made between these antiepileptic drugs (AEDs). We report a series of meta-analyses of placebo-controlled, randomized add-on trials in patients with partial epilepsy. Results of these meta-analyses are compared, thus giving broad estimates of the comparative efficacy and tolerability of these AEDs. The efficacy out come is the odds ratio for the number of patients with a ≥50% reduction in seizure frequency. Reported side ef fects are also used as tolerability outcomes, and study withdrawal is used as a global outcome measure. Results are summarized as odds ratios with 95% confidence in tervals (CIs). When each outcome is compared among drugs, the 95% CIS overlap. Therefore, no conclusive ev idence of a difference in efficacy or tolerability between these AEDs was derived, even though the apparently most effective agent (topiramate) may be twice as effec tive as the apparently least effective agent (lamotrigine). Comparative randomized studies are needed to further evaluate these drugs.     

Expanding Antiepileptic Drug Options: Clinical Efficacy of New Therapeutic Agents

Summary: Results of double-blind, placebo-controlled, add-on trials of topiramate (TPM), lamotrigine (LTG), and vigabatrin (VGB) in refractory partial epilepsy were reviewed. In three European multicenter studies of TPM, the clinical efficacy of 400–, 600–, and 800-mg/day target dosages was demonstrated. In a similarly designed United States trial, LTG was significantly superior to placebo at a 500-mg/day dosage but not at a 300-mg/day dosage. A meta-analysis of a number of smaller trials of VGB suggests that a ≥50% reduction in seizures is observed in approximately 45% of patients with refractory partial epilepsy. All of these newer antiepileptic drugs have shown efficacy in well-controlled trials and should contribute significantly to our ability to manage partial epilepsy.     

Clinical Trials of Investigational Antiepileptic Drugs: Monotherapy Designs

The standard designs for safety and efficacy trials of investigational antiepileptic drugs are placebo-controlled, add-on trials and active control equivalence studies. These designs, motivated by medical ethics, have serious evidential limitations. Add-on trials are frequently criticized as insensitive and difficult to interpret in the presence of drug interactions; active control equivalence studies are not probative of test drug activity. As an alternative, we describe two trial designs: a placebo-control design with inpatients who in undergoing a presurgery seizure evaluation have had all antiepileptic drugs discontinued; and an active-control design aimed at showing the test drug superior to the control treatment, thus avoiding the interpretational difficulties of no-difference outcomes. A critical feature of these new designs is the limitation of subject exposure to unacceptable treatments. This is accomplished through protocol criteria--corresponding to therapeutic failure--which both terminate a subject's trial participation and form the basis of efficacy comparisons.     

Clinical Efficacy of Topiramate as Add-On Therapy in Refractory Partial Epilepsy: The European Experience

Summary: In three randomized, double-blind, placebo-controlled add-on European trials, target daily topiramate (TPM) dosages of 400, 600, and 800 mg/day (200, 300, and 400 mg bid) were evaluated in adults with refractory partial seizures with or without becoming secondarily generalized. Median reductions from baseline in monthly seizure rate were 41% with TPM 400 mg/day vs. 1% with placebo ( n = 0.065), 46% with TPM 600 mg/day compared to -12% (a 12% increase) with placebo ( p ≤ 0.005), and 36% with TPM 800 mg/day versus –18% (an 18% increase) with placebo ( p ≤ 0.001). Differences between TPM and placebo with respect to percent responders (percent of patients demonstrating a 50% or greater reduction in seizures) significantly favored TPM ( p ≤ 0.05) at all three target dosages. Significant reductions in secondarily generalized tonic-clonic seizures compared to placebo were also observed with 400 mg/day ( p = 0.002) and 800 mg/day ( p < 0.05) of TPM. TPM appears to be a promising new antiepileptic drug for use as adjunctive therapy in adults with refractory partial epilepsy.     

Outcomes of Add-on Treatment with Lamotrigine in Partial Epilepsy

Summary: The need for new antiepileptic drugs (AEDs) and more sensitive methods of assessing their efficacy is well recognized. This study was designed to evaluate the efficacy and safety of lamotrigine (LTG), a potential new AED and to develop and test new outcome measures. A health-related quality of life (HRQL) model was developed which contains previously validated measures of anxiety, depression, happiness, overall mood, self-esteem, and mastery and a specifically designed seizure severity scale with patient- and caregiver-based components. This HRQL model was used in a randomized, placebo-controlled, double-blind, cross-over study of LTG in 81 patients with refractory partial seizures. Seizure frequency was the primary measure and seizure severity and the HRQL were secondary measures of efficacy. The reduction in seizure frequency with LTG, relative to placebo, was 29.7% [95% confidence interval (CI) 17.8%, 39.9%] for total seizure count, 33.4% (95% CI 14.8%, 47.9%) for complex partial seizures (CPS) and 20.3% (95% CI 0.3%, 36.2%) for secondarily generalized tonic-clonic seizures (GTCS). However, although 41 patients elected to continue with LTG, only 11 experienced at least 50% reduction in total seizures, indicating that other factors influenced their decision. The score with LTG, relative to placebo, was significantly lower for the ictal (p = 0.017) and caregivers (p = 0.035) subscales of the seizure severity scale and significantly higher for happiness (p = 0.003) and mastery (p = 0.003). Simple correlation and multiple-regression analyses indicate that the effects on seizure frequency, seizure severity, and psychological variables appear to be independent of each other. This study indicates that LTG is effective in reducing seizure frequency and has additional favorable effects on seizure severity, mood, and perceived internal control. Some of the scales used indicate the potential of secondary measures of efficacy to enhance the sensitivity of trials of new AEDs.     

Innovative Designs of Controlled Clinical Trials in Epilepsy

Summary: Uncontrolled noncomparative clinical observations of investigational antiepileptic drugs (AEDs) often lead to overoptimistic efficacy results and are therefore of very limited value for clinical AED development. The classic add-on trial with placebo as control treatment, in contrast, has provided unequivocal evidence of the efficacy of classic and new AEDs and has also identified less useful AEDs. Drug interactions, carryover effects, difficulty in analyzing individual drug action, and the recognition that monotherapy is by far the more common way of prescribing AEDs have led to the development of classic active control monotherapy trials. A major problem of these trials is a no-difference outcome, which allows no useful interpretation. Recently, two alternative monotherapy designs have been developed to avoid the deadlock of a no-difference outcome. In these designs the active control drug is administered in an attenuated form (low dosage or low concentration) or a placebo control is used when standard treatment is discontinued during presurgical evaluation. Both designs have produced unequivocal evidence of the efficacy of the investigational AED during monotherapy. Ethical concerns are minimized by the introduction of preset escape criteria for patient protection. These designs are valuable new supplements for the clinical development of investigational AEDs for monotherapy in epilepsy. In our opinion, alternative monotherapy designs should be preceded by more than one pivotal add-on, placebo-controlled trial.     

Clinical Trials of Antiepileptic Drugs Performed in the Private Practice Setting

Summary: Clinical trials of antiepileptic drugs (AEDs) are usually performed only in major teaching centers, thus ignoring the very real contribution available from private practice. The relation between the consultant and the referring family physician is often much closer in private practice, allowing much earlier recruitment of de novo patients into clinical trials. Between October 1988 and February 1992, 50 subjects were entered into various clinical trials including gabapentin (both an open add-on trial and parallel-arm add-on study in generalized epilepsies), vigabatrin (placebo-controlled cross-over study in focal epilepsies), and lamotrigine (both placebo-controlled cross-over add-on studies and parallel-arm comparative monotherapy study in newly diagnosed patients with epilepsy). All these trials were coordinated in private neurologic practice in Sydney, Australia, as part of either national or international multicenter AED studies. The experience demonstrated the improved ease of recruitment and patient liaison available in the private sector. It also highlighted the very real logistic problems, such as the need for a noninstitutional-based ethics committee, the training of support staff and a modified primary information resource system. Inclusion of private practice centers in clinical trials demonstrates the potential for improved patient recruitment and administrative management, especially in studies requiring newly diagnosed patients.     

Clinical Efficacy of New Antiepileptic Drugs in Refractory Partial Epilepsy: Experience in the United States With Three Novel Drugs

Summary: A number of new antiepileptic drugs (AEDs), including topiramate (TPM), felbamate (FBM), and gabapentin (GBP), are approved or believed to be close to approval for marketing in the United States. Key efficacy findings for these AEDs in refractory partial epilepsy were reviewed. Large and significant drug-placebo differences were observed with TPM in two large dose-finding trials conducted in the United States. The minimal effective dose of TPM in the population studied was determined to be approximately 200 mg/day, and doses above 600 mg/day produced good efficacy but little incremental benefit versus the lower dosages for the overall study population. FBM is active in partial epilepsy, although seizure reduction is less marked and drug interactions complicate the findings. GBP is also active in this population, but only the 1,800 mg/day dosage was significantly better than placebo with respect to percent re-sponders. It may be useful to explore higher dosage ranges for both FBM and GBP if they can be well tolerated.     

Effect of Acute Doses of Controlled-Release Carbamazepine on Clinical,Psychomotor, Electrophysiological,and Cognitive Parameters of Brain Function

Summary: The neurotoxic effect of acute doses of carbamazepine controlled-release (CBZ-CR) divitabs (800, 1,200, and 1,600 mg) was assessed on clinical, psychomotor, electrophysiological, and cognitive parameters of brain function in 10 healthy volunteers in a double-blind, randomised, placebo-controlled, phase I study. Significant changes compared to placebo were demonstrated for the clinical scales, ataxia (AT), convergence of the nearpoint (CNP), peak saccadic velocity (PSV), critical flicker fusion (CFF), spectral analysis of the EEG, and brainstem auditory evoked potential (BAEP) tests. Digit repetition, digit symbol substitution, Sternberg memory scanning time, Sternberg choice reaction time, saccadic latency, and saccadic accuracy showed important negative findings. Significant clinical tolerance to side effects developed within 20 to 33 h after CBZ-CR dosage during a period in which the mean CBZ blood levels remained virtually unchanged. CBZ-CR, 800, 1,200, and 1,600 mg yielded low, medium, and high therapeutic blood levels, respectively, for + 10 to + 33 h after dosage without the development of severe clinical side effects.     

Investigational Antiepileptic Drugs for the Treatment of Childhood Seizure Disorders: A Review of Efficacy and Safety

Summary: Pediatric epileptology is very different from adult epileptology. Although some epileptic disorders occur in both children and adults (e.g., localization-related epilepsy with complex partial seizures and primary generalized epilepsy with tonic-clonic seizures), other disorders can be called the catastrophic epilepsies of childhood (e.g., infantile spasms and the Lennox-Gastaut syndrome). They occur, or at least begin, exclusively in childhood and are often associated with mental retardation. Many of these pediatric disorders are notoriously unresponsive to currently available antiepileptic drugs (AEDs). Although there are undoubtedly many reasons for this, one possible explanation is that the methods used to screen potential AEDs use animal models of adult epilepsy. No screening program uses an animal model of seizures that begin during development and lead to functional decline.     

Carbamazepine and Lamotrigine in Healthy Volunteers: Relevance to Early Tolerance and Clinical Trial Dosage

Summary: This study was conducted to examine the effects of acute doses of lamotrigine (LTG) and carbamazepine (CBZ) in healthy subjects and determine whether the low tendency to impairment with LTG observed in animals applied to humans. Twelve healthy men participated in a placebo-controlled, balanced, doubleblind comparison of the drugs on a series of psychomotor, autonomic, sensory, and subjective variables. Variables were analyzed by analysis of variance, and p < 0.05 was considered significant. Adaptive tracking and body sway were impaired by CBZ 600 mg. CBZ 400 and 600 mg impaired smooth pursuit eye movements and also reduced mean peak saccadic velocity. No differences from placebo occurred after LTG. CBZ 600 mg increased heart rate (HR), but no drug-related changes were noted in pupil size, salivary secretion, visual near point, or subjective effects. During the controlled study, mean plasma CBZ concentrations at 2 and 6.5 h after the 600-mg dose were 5.28 and 5.36 μg/ml; after LTG 300 mg, they were 3.16 and 3.00 μg/ml. Increased CBZ saliva concentrations were significantly associated (p < 0.01) with impaired adaptive tracking, smooth and saccadic eye movements, and increased HR, and plasma concentrations were associated with impaired eye movements and body sway.     

Double-Blind Study of Gabapentin in the Treatment of Partial Seizures

Forty-three patients completed a double-blind, placebo-controlled study of Gabapentin (GBP) as add-on therapy in partial and secondarily generalized seizures. All patients were followed for an initial 3-month baseline period, after which they were randomly allocated to receive either a placebo or 900 or 1,200 mg/day GBP for 3 months. A statistically significant difference in seizure frequency from the baseline to the treatment phase was noted between patients receiving placebo and GBP 1,200 mg, in whom seizure frequency decreased 57%. The GBP dosage of 900 mg appeared to be ineffective. A close relationship was observed between the serum GBP concentrations and the GBP dosage based on the seizure frequency. Serum GBP concentrations greater than 2 micrograms/ml resulted in a lower frequency of seizures. The adverse effects were minor and consisted mainly of transient drowsiness. GBP appears to be effective in the treatment of partial epileptic seizures in a dosage-related manner.     

Prototype Antiepileptic Drug Clinical Development Plan

Antiepileptic drug (AED) development has been generally difficult owing to many factors: regulatory requirements for demonstration of efficacy and safety, subject availability, traditional trial designs, and physicians' beliefs about epilepsy and its treatment. The U.S. Food and Drug Administration (FDA) regulations require a new drug to be shown safe and effective for its intended use before it can be marketed. The unambiguous proof required is a formidable hurdle for AED development. We report a recent clinical development plan highlighting innovations in clinical trial design that have addressed these requirements, discuss alternative endpoints, and compare the results of various trial designs at various stages of development. This model clinical development plan includes trials relevant to all three clinically relevant contexts in which an AED might be used: as an adjunct to an existing regimen, as a substitution for much of an existing AED regimen, and as monotherapy.     

Clinical Experience with Oxcarbazepine

Summary: Controlled studies of oxcarbazepine (OCBZ) and the largest of the open studies of OCBZ were reviewed. The overall results indicated that OCBZ has the same clinical effect as carbamazepine (CBZ) but causes fewer adverse effects. Studies of allergic toxicity seem to indicate that OCBZ may be tolerated in the majority of patients developing allergy towards CBZ. We concluded that OCBZ is a drug of first choice for the treatment of epilepsy.